Grants

NCI - National Cancer Institute

Project Summary Breast cancer related lymphedema (BCRL) is a chronic, incurable condition that negatively impacts quality of life due to abnormal swelling causing arm/chest tightness, heaviness, pain, and impaired limb function. BCRL is typically diagnosed by a 5-10% increase in relative arm volume after irreversible fluid accumulation and tissue swelling occurs. Complete decongestive therapy, consisting of a regimen of manual lymphatic drainage, compression bandaging, and skin care forms the basis of lymphedema treatment and has largely remained unchanged for decades. Intervention at first diagnosis, based on limb volume, with continued patient compliance results in better outcomes for patients but is not curative. Recent studies using near-infrared fluorescence lymphatic imaging (NIRF-LI) indicate that lymphatic dysfunction, in the form of dermal backflow, can be screened on average, approximately eight months prior to conventional clinical BCRL diagnosis, based on limb volume. Importantly, lymphatic dysfunction was reduced after just two weeks of daily physical rehabilitation in 75% of patients recently diagnosed with early head and neck cancer-related lymphedema. We hypothesize that early physical rehabilitation with advanced pneumatic compression, provided at the first sign of lymphatic dysfunction and before the onset of BCRL, may resolve lymphatic dysfunction. This will prevent the development of lymphedema and enhance the quality of life in breast cancer survivors. Our specific aims are, (1) Longitudinally assess lymphatic dysfunction in breast cancer survivorship using 3D qNIRF-L, (2) Assess impact of early physical rehabilitation on lymphatic dysfunction in cancer survivorship, (3) Assess the durability of lymphatic response to early physical rehabilitation. We expect that early physical rehabilitation will decrease or ameliorate lymphatic dysfunction reducing the incidence of lymphedema and that these changes will be durable and curative, with permanent restoration of lymphatic function. The collaborations include MPIs at M.D. Anderson Cancer Center, which treats advanced breast cancer patients at highest risk for lymphedema, and at UTHealth, where translation of NIRF-LI originated, as well as collaboration with the University of Houston for data analytics. If successful, the clinical trial conducted in this project will provide objective criteria for early deployment of physical rehabilitation to prevent cancer-acquired lymphedema before its irreversible onset, improving the quality of life of cancer survivors while demonstrating a simple, point-of-care strategy for archival documentation of subclinical lymphatic dysfunction.

Up to $664K

2031-04-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Impact of Mandatory NIH Neuroethics Requirements

NIMH - National Institute of Mental Health

PROJECT SUMMARY Human subjects research with novel neural devices raises unique ethical issues, such as post-trial responsibilities, privacy of brain data, and atypical risks such as changes to personality. To manage the discrepancy between research practices and ethics oversight, in 2018 the NIH added a mandatory neuroethics section to a subset of neuroscience grants in addition to the standard protection of human subjects component. However, despite the unique nature of this requirement, to date there have been no systematic efforts to assess stakeholders’ experiences with and attitudes toward these mandates. This represents both a critical gap and opportunity. Without empirical research evaluating the impact of neuroethics mandates, we risk implementing ineffective requirements, lack the information needed to make useful modifications, and remain unaware of their strengths and weaknesses. Furthermore, given that there is no established pathway nor guidance for investigators to address neuroethics requirements, examining researchers’ experiences offers a valuable opportunity to understand how they devise neuroethics plans as well as barriers they might encounter when implementing them. The overall objective of this short-term R21 exploratory proposal is to assess the impact of mandatory NIH neuroethics guidelines on the ethical design and conduct of brain-related research and to identify effective strategies that investigators have utilized to address neuroethics in their research. This will be achieved through two complementary aims that involve interviewing researchers who have been funded through NIH grants requiring neuroethics sections (Aim 1) and surveying those who review neuroethics components of grant applications (Aim 2). This project directly addresses the broad area of RFA-MH-25-171 (“enhance integration of neuroethics and neuroscience”). The expected outcomes of this two-year exploratory R21 project are a set of multistakeholder perspectives on the impact of neuroethics mandates and recommendations for improving them, an identification of strategies that researchers have utilized to address neuroethics mandates, and a determination of areas of unmet needs regarding resources for addressing neuroethics requirements. Our findings will benefit funders, by providing insights into the impact of neuroethics requirements and recommendations for improving them; researchers, by providing a set of effective strategies that have been used to address neuroethics sections; neuroethicists, by determining areas of unmet need regarding neuroethics resources; and the public, by identifying pathways for enhancing the ethical conduct of neurotechnology research. This project is significant because it has the potential to impact the way that the ethics is integrated and assessed across BRAIN Initiative research and in other scientific endeavors.

Up to $221K

2028-02-29

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Impact of Psychosocial Risks Among Veterans on Complications of Major Cancer Surgery

NIH

Significance to the VA: Complications following major cancer surgery occur in over 30% of cases and have a major impact on quality of life and disease-free survival. Having two or more psychosocial risks independently confers a 3.4-fold increase in the odds of a postoperative complication. While this association has been established, it is not yet known which psychosocial risks are most associated with surgical complication and which risks are acutely modifiable. Psychosocial vulnerability in the immediate postoperative period substantially complicates care delivery. Housing instability and other psychosocial risk factors (food insecurity, mental health comorbidities, and criminal justice involvement) are not routinely screened for in surgically treatable disease. The long-term goal of this proposal is to address gaps in cancer surgery care by developing psychosocial support interventions that reduce surgical complications ultimately improve cancer survival. Innovation and Impact: Although preoperative optimization programs recognize the importance of risk stratification and potential psychosocial needs, there is limited evidence for which risk factors to target and to what degree these risks are modifiable. This study will inform the best means to identify psychosocial risks among patients undergoing cancer surgery using existing VA data and identify those factors most strongly associated with perioperative complications. We intend to use these findings in future work to then identify a broad set of intervenable psychosocial risk factors for veterans undergoing cancer surgery. Specific Aims & Methodology AIM 1. Compare detection of housing instability and other psychosocial risk factors in veterans undergoing major cancer surgery using structured data elements versus natural language processing (NLP). Using a national cohort (10,000+ per year of analysis, 2008-2022) of elective cancer surgery patients, housing instability and other psychosocial risk factors will be assessed using conventional definitions of these risks in VA structured data fields. Identification of housing instability and other psychosocial risk factors will also be performed using an internally developed NLP algorithm that incorporates a supervised machine learning algorithm. Finally, 100 discordant cases (structured vs. NLP) will be used to compare performance. AIM 2. Compare the association of postoperative complications and alternative measures of housing instability and other psychosocial risk factors in veterans undergoing major cancer surgery. We will use the enhanced cohort from Aim 1 that combines surgical outcomes data with new definitions of housing instability and other psychosocial risk factors to test for the independent association between psychosocial risk and worse outcomes after surgery. AIM 3. To tailor and pilot via expansion of an existing intervention (renamed Surgical Vulnerability Program, SVP) to mitigate the effects of perioperative psychosocial risk on postoperative complications following major cancer surgery. Informed by Aims 1 and 2, we will recruit 30 patients enriched with psychosocial risks identified by the outperforming approach and tailor an existing intervention better support these patients through the perioperative period. Care partners will be interviewed to evaluate feasibility, acceptability, and perceived utility. Pathway to Translation/Implementation: A more accurate delineation of psychosocial risks and a clear association with postoperative complications will better characterize preoperative surgical risk as well as its potential modifiability. A “better” designation of psychosocial risk will facilitate targeting social support interventions in the pre- and postoperative period that mitigate their impact on surgical outcomes. Moreover, the use of NLP algorithms to identify novel psychosocial risk factors prior to surgery will allow for high- throughput, nationwide risk stratification and opportunity to intervention.

2031-06-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the longitudinal impact of Mediterranean diet interventions to reduce cognitive decline on gut microbiota composition and bile acid variety

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is a progressive neurodegenerative disorder with a complex etiology affecting over six million individuals in the United States alone, with numbers projected to rise significantly as the population ages. Concomitant changes in gut microbiome and metabolome composition have been observed over the course of Alzheimer’s-related cognitive decline, suggesting host microbiota may mediate the pathophysiological processes of Alzheimer’s disease and related dementias. Gut microbes contribute to host metabolism through the production and modification of metabolites, such as bile acids, which collectively influence overall metabolic health. Lifestyle interventions, such as diet modification, are promising strategies for lowering dementia risk, and these modifications are also influential in regulating the gut microbiome. However, the long-term effects of specific dietary interventions on microbially-mediated bile acid profiles and their impact on cognitive decline remain poorly understood, motivating further investigation. This proposal seeks to apply advanced computational and algorithmic approaches to identify compositional and functional changes in the gut microbiome and metabolome over the course of longitudinal dietary interventions. Aim 1 of this proposal will unify three independent cohorts assessing the impact of adherence to the Mediterranean diet, a diet high in plants and healthy fats, on cognitive decline. By conducting phylogenetically-aware metagenomic analyses and network-based untargeted metabolomic analyses, this proposal aims to identify changes in microbial communities and bile acid profiles during Mediterranean dietary interventions, and correlate these changes with host phenotypes indicative of Alzheimer’s risk. Complementarily, Aim 2 of this proposal will assess the prognostic potential of gut microbiome and metabolome features by constructing and evaluating machine learning models to predict cognitive outcomes over the course of intervention. These efforts will deepen our understanding of the relationship between diet, the gut microbiome, bile acid proliferation, and cognitive health by employing standardized and reproducible methodological analyses across large cohorts. Ultimately, this research is poised to reveal mechanistic targets for future study, facilitating the development of novel diagnostic and therapeutic strategies for Alzheimer's disease in at-risk populations.

Up to $44K

2030-02-01

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Risk of Fetal Fentanyl Syndrome Amid the Ongoing Fentanyl Epidemic: A Comprehensive Approach Using Diverse Data and Methods

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Fentanyl is a potent synthetic opioid used for the treatment of severe pain. It is also responsible for a large proportion of illicit opioid use and overdose deaths in the United States. The fentanyl epidemic affects young women and spills into pregnancy such that opioid-related overdoses are now a leading cause of maternal mortality. Moreover, in 2023, a report of ten cases suggested that maternal abuse of fentanyl during pregnancy causes a pattern of structural abnormalities referred to as “Fetal Fentanyl Syndrome (FFS)” characterized by distinctive facial features and congenital anomalies of hands and feet. In response, NIDA issued a Notice of Special Interest (NOT-DA-26-003: Consequences of Prenatal Fentanyl Exposure) to promote research on the potential teratogenic effects of prenatal fentanyl exposure in humans. We propose to assess the effect of maternal fentanyl use during pregnancy on the risk of specific congenital malformations in general, and the risk of FFS in particular. The project will use four coordinated and complementary approaches that allow evaluation of both illicit and prescription fentanyl use. Aim 1 will use proxies for illicit fentanyl uptake obtained from national databases (e.g., fentanyl overdose deaths) to create a temporo-spatial instrumental variable and evaluate its association with FFS rates in the population. This innovative ecological approach avoids confounding at the individual level (e.g., by alcohol exposure). Aim 2 will use a unique linkage between birth defects and neonatal abstinence syndrome surveillance programs in several US states to evaluate the association between maternal and infant toxicology screens positive for fentanyl and FFS. Aim 3 will use data from the FDA Adverse Events Reporting System to assess whether FFS was disproportionally reported for prescription fentanyl relative to other opioids in the time period prior to the medical community having been alerted to the syndrome. Aim 4 will use data obtained from nationwide healthcare utilization databases of publicly and commercially insured pregnancies linked to newborns to compare the risk of FFS for prescription fentanyl during pregnancy relative to other prescription opioids. This study will be designed as a target trial emulation and will use advanced analytic methods to minimize biases. For all aims, FFS cases (reports, clinical records or claims profiles) will be adjudicated by dysmorphologists. The interpretation will consider timing of exposure during pregnancy, potential dose-response and the potential role of adulterants in illicit fentanyl. Each approach provides a unique lens through which to examine the question, and together, they will strengthen our confidence in the conclusions drawn. Our proposal benefits from the collective experience and established track record of a multidisciplinary team, and our prior work and preliminary assessments attest to the project's feasibility. Ultimately, completion of this research will contribute information to our understanding of fentanyl’s teratogenic risk in humans and inform clinical guidelines and pregnancy safety narratives in drug labels.

Up to $795K

2031-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Role of Cannabis in Sober Living Houses

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Some studies suggest that cannabis is a safer substitute for other substances, including for those with substance use disorders (SUD). Historically, sober living houses (SLHs) have been abstinence-based environments for individuals in recovery to live with others in recovery, yet mixed evidence regarding cannabis substitution along with rapidly changing laws have left SLHs in a difficult position regarding policies related to cannabis use among residents. Furthermore, few studies have examined cannabis use among specific populations of individuals with SUD or among those embarking on recovery from SUD. The proposed study, Assessing the Role of Cannabis in Sober Living Houses will address these issues via three specific aims: Aim 1 will examine how cannabis use is related to alcohol or other drug use, mental health, and recovery capital outcomes among SLH residents. Aim 2 will assess why individuals who live in SLHs use cannabis, medical cannabis use, how these are related to outcomes, and how these align with their recovery and living in an abstinence-based environment. Aim 3 will identify the range of current cannabis use policies and practices in SLHs and begin to develop an SLH policy assessment tool. This study requires the recruitment of SLHs (N=35), SLH managers, and SLH residents (N=400; 200 in recent cannabis use group, 200 in non-recent cannabis use group). Aim 1 involves following a prospective cohort of 400 residents, where exposure is defined by cannabis use in the past 30 days, and collecting data longitudinally over three time points across 12 months from both the use and non-use groups. Aim 1 analyses are all quantitative. Aim 2 is mixed methods and involves (1) quantitative analyses assessing how reasons and motivations for cannabis use are related to outcomes and (2) qualitative interviews focused on motivations for cannabis use and views regarding cannabis’ role in recovery. A focus of Aim 2 is medical cannabis use. Finally, Aim 3 involves qualitative interviews with house managers to document SLH cannabis policies. After analyses for all aims are complete, we will hold focus groups with house managers, residents, and our community advisory board to interpret findings, develop future research questions, and begin forming recommendations for dissemination to SLHs. The definition of SUD recovery is evolving, and how cannabis use might affect specific subpopulations of individuals with SUD, e.g., SLH residents, remains an open question as research on cannabis use in other populations might not apply to this population. Thus, if SLHs base policies on research from other populations, some residents might risk their recovery efforts. As more states legalize cannabis and the tension increases between proponents of abstinence and harm reduction, the question of how SLH operators should address cannabis is becoming more pressing. This project will also be the first to document cannabis use policies in SLHs, including issues and challenges faced by house managers in implementing these policies. Findings will enable service providers to develop policies that best support SLH residents and managers.

Up to $542K

2031-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Role of Gastrointestinal Mechanosensation in the Regulation of Feeding Behavior and Glucose Homeostasis

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Obesity has risen drastically in recent decades within the United States, underscoring a critical need for more effective therapies. Despite the significant progress that has been made within the obesity research field, effective therapies for obesity are still lacking. This demonstrates the need for interventional strategies that effectively reduce body weight and maintain weight loss. Vagal afferents within the nodose ganglia (NG) that terminate in the gut (and other peripheral organs), sense postprandial signals and then relay that information to the neurons in the nucleus of the solitary tract (NTS) of the brain, a region critical for integrating peripheral signals and initiating changes in feeding behavior and glucose homeostasis. It is appreciated that disruptions in gut-brain communications like vagal afferent signaling, contribute to the pathophysiology of obesity. Vagal afferent neurons that express oxytocin receptor (OxtR) are primarily responsible for sensing stretch in the intestine and have been shown to regulate energy and glucose homeostasis. Specifically, my preliminary data demonstrates that intestinal stretch reduces food intake and that this effect is dependent on vagal OxtR signaling in female but not male mice. Intestinal stretch also increases oral glucose tolerance in male and female mice. We have also shown that diet induced obese mice of both sexes lack intestinal stretch-induced reductions in food intake and improvements in oral glucose tolerance. Lastly, intestinal stretch significantly reduces glucose levels via increased insulin secretion independent of vagal OxtR in both male and female mice. Our overarching hypothesis is that dysfunctional intestinal mechanosensation impairs satiety and glucose homeostasis in a sex-specific manner. This hypothesis will be tested using the following aims: Aim 1) To define role of vagal OxtR neurons and their central targets in regulating energy homeostasis in obesity and Aim 2) To elucidate vagal and endocrine mechanisms by which intestinal stretch regulates glucose homeostasis. Through the K01 training plan, I will master chemogenetics, single-cell transcriptomics, microsurgeries, and metabolic phenotyping, positioning me to establish an independent program dedicated to gut-brain regulation of energy and glucose balance. By clarifying how intestinal mechanosensation governs feeding and glycemic control, and how these pathways fail in obesity, this project will lay the groundwork for precision gut-targeted interventions that can sustain weight loss metabolic health.

Up to $132K

2029-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the Role of HIV-specific IgA glycosylation on transport and function

NIAID - National Institute of Allergy and Infectious Diseases

Summary/Abstract: The advent of antiretroviral therapy (ART) has transformed HIV infection from a fatal disease into a manageable chronic condition. However, people living with HIV continue to experience comorbidities linked to persistent immune activation and inflammation. Unfortunately, there is not a functional vaccine for HIV, and recent efforts to achieve protection through passive immunization with broadly neutralizing anti-HIV IgG antibodies have not been successful. One promising avenue is anti-HIV IgA immunotherapy. Our recent published findings demonstrate that intrarectally applied anti-HIV IgA has an effect on the dissemination of HIV to lymph nodes following intra-rectal challenge. Elucidating the role of biochemical properties, such as glycosylation, on regulating the transport and effector functions of anti-HIV IgA remains poorly understood and requires further investigation. Our previous studies demonstrate that the glycosylation pattern of an anti-HIV IgG monoclonal antibody can influence its ability to disseminate across the blood brain barrier. In addition, we found that glycoengineered IgA isolated from colostrum exhibit altered transport properties. Taken together, these findings support our hypothesis that the glycosylation of IgA influences its cellular transport and can be strategically modified to enhance its transcytosis and function. In aim 1 we will characterize the glycosylation patterns of bulk IgA isolated from people living with HIV and compare them to non-HIV controls. We will then assess how these glycosylation profiles influence endothelial transport and how these changes correlate with viral load. In aim 2 we will clone anti-HIV monomeric IgA and express in 293 freestyle cells that have glycosl- transferases knocked down in order to create glycoengineered IgA. We will define the optimal glycosylation patterns that maximize endothelial transcytosis and antiviral effector functions. We have assembled a team of investigators uniquely equipped to carry out the aims of this grant.

Up to $270K

2028-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the role of lncRNA SLAMR in the pathogenesis of Alzheimers disease

NIA - National Institute on Aging

SUMMARY The functions of long-noncoding RNAs (lncRNAs) as crucial regulators of transcription, epigenetic modifications, mRNA stability, localization, and translation indicate their potential involvement in Alzheimer's disease (AD) pathogenesis. Given the impairment of these fundamental cellular processes in AD, lncRNAs emerge as plausible targets. Consistent with this possibility, several studies have demonstrated altered expression of specific lncRNAs in various AD models. However, the precise roles, mechanisms, and cell-specific contributions of these lncRNAs in AD development remain unclear. This exploratory/developmental R21 proposal aims to systematically investigate the regulation of expression and function of lncRNA SLAMR in the pathogenesis of AD. SLAMR lncRNA was discovered from an unbiased screen of learning regulated lncRNAs. We find that SLAMR lncRNA in mouse CA1 is critical for synapse density, morphology, plasticity and memory. Importantly, we find that SLAMR functions as a key modulator of translation and structural plasticity. Gain of function of SLAMR resulted in enhanced translation and functional synapses. Our preliminary data show that SLAMR expression is impaired in APP knock-in (App NL-G-F) mouse model of AD. We will now assess the role of SLAMR mediated translation in App NL-G-F model and Tau model (PS19) of AD. Our systematic functional experiments are anticipated to unveil the role of SLAMR in the progression of AD pathogenesis. Successful completion of this proposal will shed light on the significance of lncRNAs in AD pathogenesis and influence the development of lncRNA-based therapeutics for AD.

Up to $507K

2028-01-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing the tolerability and versatility of the new Spytag003/Spycatcher003 as a novel bio-conjugation system for displaying protein antigens on the surface of bacteriophage VLPs

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Peptide and protein antigen vaccines are very safe compared to live-attenuated vaccines. They can be used to immunize anyone and are not associated with a lot of side effects compared to live-attenuated vaccines. However, peptides and proteins are less immunogenic compared to live-attenuated vaccines. To overcome these limitations, peptide antigens have been inserted/displayed on the surface of virus-like particles (VLPs) to increase their size as well as the valency or density of the peptide. VLPs are morphologically and structurally similar to viruses from which the coat proteins are derived from, except for the fact that they lack the viral genome. VLPs are highly immunogenic even at small doses of antigens. Most peptide antigens can be displayed on VLPs by genetic insertion or by chemical conjugation (to make them multivalent and highly immunogenic). However, these two approaches cannot be used for every peptide not to mention protein antigens. The size of an antigen as well as the composition of the antigen most of the time interferes with these two conjugation approaches. These limitations make in very impossible to use identified antigens with neutralizing and protective epitopes in vaccine design. To overcome the limitations with genetic and chemical conjugation approaches, we propose to explore a novel bio-conjugation approach on 4 bacteriophage VLPs (MS2, PP7, AP205, Q). This approach will use the new Spytag003/Spycatcher003 bio-conjugation system developed from the prototype Spytag/Spycatcher. In the proposed study, we will assess the potential of using the new Spytag003/Spycatcher003 bio-conjugation system to display diverse protein antigens on the surface of 4 bacteriophage VLPs. We will assess the versatility of the new bio-conjugation system on these VLPs using diverse protein antigens that differ in origin, size, and conformation.

Up to $588K

2029-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessing Toxicology Testing Practices by Medical Examiners and Coroners during the Opioid Crisis

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT We propose a study to assess medical examiner and coroner (MEC) office triaging practices for deciding which suspected overdose death investigation cases receive toxicology testing. U.S. federal, state, and local governments make important policy and funding decisions based on the number of overdose deaths annually, but these figures are based on MEC determinations that the cause of death is a drug overdose. Experts acknowledge that overdose mortality numbers are incomplete and inaccurate based on unstandardized, local determinations made by an under-resourced patchwork of an estimated 2,000 U.S. MECs. Thus, toxicology testing cannot be performed commensurate with minimum recommended standards, necessitating MEC triaging. We define medicolegal death investigation triage to be the process MECs use to prioritize conducting toxicology testing for decedents suspected to have died of a drug overdose. Although triage practices for overdoses help maximize MECs’ limited toxicology testing capabilities, they are varied, unstandardized, and understudied. An examination of the triaging practices that exclude toxicology testing is missing, which is crucial for assessing whether these strategies deliver the mortality data required for effective decisions and public health monitoring. The Delivery Systems Framework will guide our evaluation of MEC triage practices to meet the following aims: (1) Develop a medical examiner/coroner triaging typology by assessing their extant triage practices as they investigate potential overdose fatalities; (2) Determine what medical examiner/coroner organizational characteristics are associated with triaging and triaging typologies; and (3) Determine the overall national error rate for triaged overdose cases and how error rates vary by drug toxicology triaging typology and organizational characteristics. To achieve Aims 1 and 2, we will survey a random national sample of 500 MEC offices on factors associated with triaging practices. This will allow us to create a typology of common triage practices that drive toxicology testing decisions for suspected overdose cases (Aim 1) and determine what MEC characteristics are associated with these triaging typologies (Aim 2). To achieve Aim 3, we will partner with Axis Forensic Toxicology and 40 diverse MECs to conduct toxicology testing on 1,000 reported overdose cases that did not originally receive toxicology tests given these MECs’ triaging practices. We will evaluate the accuracy of triage decisions with the newly obtained toxicology findings (i.e., decision not to test but drug(s) were detected). The proposed new Principal Investigator (sociologist Smiley-McDonald) is joined by a forensic toxicologist (Ropero-Miller), an epidemiologist (Kral), a statistician (Williams), and a medicolegal death investigator (Keyes). The study will provide an evidence base for identifying effective triage practices, which will in turn improve future mortality data. Improved mortality statistics will allow governments at all levels to make informed decisions and better mobilize public health resources and overdose response.

Up to $637K

2029-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation

NIAID - National Institute of Allergy and Infectious Diseases

Current standard of care for kidney transplant (KTx) recipients has only modestly improved long-term aggregate graft and/or patient survival, identifying a crucial unmet medical need. As the at-risk KTx population is heterogeneous, the currently employed and relatively homogeneous therapeutic approach to immunosuppression in KTx in the US and Canada is suboptimal, and results in a significant proportion of over- immunosuppressed recipients, many with tacrolimus-related toxicities. In this U01 application, Co-PIs Heeger and Nickerson will build upon their past, productive collaborative efforts, their established multicenter trial consortium and infrastructure, as well as their expertise in biomarkers and mechanistic studies to address this unmet need. The overarching goal of the proposed work is to determine the utility of the HLA-DR/DQ molecular mismatch (mMM) score, as a risk stratifying biomarker in KTx. While retrospective studies showed strong correlations between the HLA-DR/DQ mMM score and the risk of developing biopsy proven acute rejection (BPAR) and/or donor specific antibodies (DSA), no prospective studies have tested the HLA mMM score as a risk stratifying biomarker for immunological KTx injury. Nor have any studies attempted to test whether and how the HLA-DR/DQ mMM score performs as a predictor of outcome following a change in transplant immunosuppression. Herein, we propose a multicenter observational study with a nested randomized controlled (RCT) trial to address these deficiencies. We will prospectively test the utility of the HLA-DR/DQ mMM score as a prognostic biomarker of primary alloimmunity [T cell mediated rejection (TCMR), DSA, and antibody mediated rejection (ABMR)] in KTx (Aim 1, observational study of 800 KTx). We will also test the hypothesis that the HLA-DR/DQ mMM score is a predictive biomarker that identifies KTx recipients who will tolerate substituting the calcineurin inhibitor with self-administered, subcutaneous abatacept (costimulatory blockade), without an unacceptable increased risk of BPAR, while reducing the morbidity of CNI off-target effects (300 KTx, Nested RCT with a non-inferiority endpoint, Aim 2). Accompanying mechanistic studies (Aim 3) will provide novel immunological and molecular insights that will also aid in interpreting graft and recipient outcomes of the trial. If successful, the work will provide crucial information capable of positively, and directly affecting clinical care. The results from the proposed work also have the potential to influence positively the design of future RCTs by providing an HLA-DR/DQ mMM score-based stratification or enrichment strategy for enrolling subjects into trials most likely to be informative for the proposed study agent-- thereby increasing likelihood of trial success in the shortest possible time.

Up to $50K

2029-06-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessment of Body Composition in Adolescents with T2D on Glucagon-like-peptide receptor agonists (GLP-1RAs) (ABC Study)

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The prevalence of type 2 diabetes (T2D) is increasing in adolescents, and metformin, the first-line FDA-approved therapy for T2D, often fails to achieve durable glycemic improvement. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide have transformed the treatment landscape, offering substantial benefits, including weight loss, glycemic improvement, and β-cell preservation. However, their unintended effects on skeletal muscle loss and eating behaviors in adolescents remain poorly understood. Understanding these benefits is crucial for optimizing treatment safety and efficacy during adolescence, a key developmental period. To address this unmet medical need, Sujatha Seetharaman, MD, proposes a study through this career development with the following aims (1a) assess changes in body composition and functional outcomes over six months of semaglutide therapy in adolescents with T2D (1b) examine how the rate of weight loss with semaglutide relates to changes in muscle mass in adolescents with T2D (2) investigate the effect of semaglutide on the risk of disordered eating and internalized weight stigma in adolescents with T2D. She will enroll 50 adolescents (ages 12–17.99 years) with new-onset T2D from UCSF Diabetes Clinics, treated with metformin for at least 3 months, and initiating semaglutide per their routine clinical care. In aim 1, she will assess changes in fat mass using magnetic resonance imaging, skeletal muscle mass using the D3 creatine dilution method, muscle quality, strength, and function at baseline and 6 months. In aim 2, she will calculate the rate of weight loss over 6 months and correlate it with skeletal muscle mass loss, strength, and function. In aim 3, she will examine changes in eating attitudes and internalized weight-related stigma at baseline and at 6 months to identify individuals who are at risk for disordered eating. Results from this proposal will inform an R01 in which targeted interventions such as an integrated exercise program and eating disorder prevention strategies will be tested in a large randomized controlled trial and expanded to include emerging dual/triple agents in adolescents with T2D. Dr. Seetharaman’s long-term career goal is to become an independently funded clinician-investigator advancing research that integrates novel pharmacotherapies with tailored interventions to improve health outcomes in adolescents with T2D. In this career development award, her career goals are to gain targeted training in body composition analysis, become proficient in advanced biostatistical methods, become proficient in utilizing person-reported outcome metrics, gain experience in conducting pediatric clinical trials, and engage in career development activities in preparation for R01 funding. She will accomplish these goals with the advice and mentoring from a world-class multidisciplinary mentoring team, participation in relevant didactic coursework, and hands-on research experience, all necessary for future independent success. This project aligns with NIDDK’s mission to improve the health and well-being of individuals affected by diabetes and related conditions.

Up to $203K

2031-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessment of developmental milestone attainment in electronic health record-derived tic disorder patients

NIMH - National Institute of Mental Health

PROJECT SUMMARY Motor and vocal tics are defined by repetitive, uncontrollable movements or sounds and are a common feature of childhood developmental disorders. Although tics impact the lives of 1-2% of children and increase the risk for disabling neurological and psychiatric conditions later in life, tic disorder research has been hindered because of the small number of patients enrolled in research studies. To improve the lives of tic disorder patients and address this burden to public health, it is critical that we expand our research to larger populations. This proposal addresses this limitation by introducing the use of existing electronic health record data as a cost-effective way to analyze detailed patient information across the lifespan of individuals with tic disorders. We have assembled a research team that is well suited to perform these studies, including researchers and specialized clinicians with extensive experience in analyzing electronic health record data and expertise in the diagnosis and treatment of complex neurodevelopmental conditions, including tic disorders. First, we will design an algorithm to identify individuals with evidence of a tic disorder diagnosis by systematically searching for specific patient characteristics across the medical records of 3.8 million patients. We will then evaluate the performance of this algorithm using clinical expertise and a validated set of tic disorder patient records. Next, we will use information from medical records to examine whether delays in early childhood development are observed in tic disorder patients. Pediatric milestone data is collected on all children at well-care visits from birth to early childhood and includes direct reporting from parents and physicians assessing the child's ability to achieve standardized motor, social, and language skills (e.g. sitting, crawling, walking, smiling, pointing, name-recognition). This dataset provides a rare opportunity to examine whether individuals with tic disorders show developmental delays that predate the onset of tic symptoms. Lastly, we will look at whether the timing of developmental milestone attainment is associated with specific health outcomes in tic disorder patients. The deliverables from this study include cu ration of a large dataset of clinically validated tic disorder patients that will serve as a valuable resource for future investigations. Additionally, this study will provide the first systematic evaluation of developmental milestone attainment in tic disorder patients at this scale. By harnessing the power of large-scale electronic health record data, we can evaluate the clinical features underlying tic disorders across the lifespan, ultimately leading to better-informed personalized care and decreased burden on patients and their families.

Up to $175K

2028-06-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

Assessment of efflux transport, pharmacokinetics and systems pharmacology impact on MMAE induced neurotoxicity

NCI - National Cancer Institute

ABSTRACT Exposure to Monomethyl Auristatin E (MMAE), following antibody-drug conjugate (ADC) treatment, has been linked to neurotoxicity in approximately 50% of patients that is commonly irreversible and can have substantial impact on cancer survivor quality of life or prompt discontinuation of life-saving therapy. Therefore, the long- term goal associated with this proposal is to improve therapeutic outcome by abolishing ADC-mediated peripheral neuropathy. The overall objective of this proposal is to uncover novel signaling pathways that influence the development of MMAE-induced peripheral neuropathy, as well as assess the role membrane transporters in regulating this adverse event. The central hypothesis is that analysis of interactions following peripheral nervous system drug exposure using a network-based systems pharmacology model will reveal a combination of targets that can mitigate neurological side-effects of MMAE-based therapy, and that P-gp regulates the severity of MMAE-induced neuropathy. The rationale for this project is that identification of proteins that regulate MMAE-induced neuropathy would provide a pharmacological target to abolish a devastating adverse event or predict interpatient variability through genetic variation or drug-interactions associated with these proteins. The central hypothesis will be tested by pursuing two specific aims: i) Evaluate P-gp as a factor that regulates MMAE pharmacokinetics and disposition into peripheral nerves along with peripheral neuropathy; and ii) Identify signaling changes in peripheral nerves by MMAE using a systems pharmacology network-based model. Under the first aim, in vivo and ex vivo P-gp genetic knockout mouse models will be used to measure the ability of this transporter to modulate MMAE disposition and neuropathy. Additionally, we will evaluate the role of other transporters in regulating MMAE DRG sensitivity. Under the second aim, drug pharmacokinetics, along with signaling network changes coupled with patterns of differentially expressed genes in peripheral nerves exposed to MMAE will be used to develop a systems pharmacology network-based model. Simulations and analyses of the model will identify interventions in the network that would provide protection from MMAE neurotoxicity. The research proposed in this application is innovative because it represents a substantive departure from the status quo by measuring the involvement of a drug transporter in regulating MMAE toxicity instead of efficacy, along with establishing multiple signaling events or potential molecular targets that could predict or ameliorate this adverse event. The proposed research is significant because it is expected to identify P-gp as a transporter that is genetically variable among patients and susceptible to drug interactions, and could therefore be assessed to predict the severity of, or prevent, MMAE neurotoxicity. Additionally, our systems pharmacology model is expected to identify protein networks that can be manipulated to ameliorate this adverse event. Ultimately, such knowledge is predicted to reduce the number of patients who would experience a toxicity that can impact quality of life or become life threatening through dose reduction or cessation of cancer therapy.

Up to $411K

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Assessment of Everolimus as a Therapy for Vici Syndrome in a Preclinical Model

NCATS - National Center for Advancing Translational Sciences

PROJECT SUMMARY/ABSTRACT Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immunodeficiency, cardiomyopathy, and progressive motor decline, with a median survival of just 42 months, This devastating disorder is caused by pathogenic variants in the EPG5 gene, which encodes a critical regulator in autophagy. Loss of EPG5 function results in the accumulation of toxic intracellular material and progressive cellular dysfunction. VS is a member of a broader class of diseases known as 'Congenital Disorders of Autophagy' (CDAs), in which core components of autophagy are defective. There are essentially no treatment options for children with VS or other CDAs. We hypothesize that agents that induce pharmacological enhancement of autophagy in VS and other CDAs represent a viable therapeutic strategy. In collaboration with VS families, we have developed and characterized critical preclinical models for VS for therapeutic discovery and validation, including patient-derived induced pluripotent stem (iPS) cells and novel genetically engineered mouse models. These Epg5 mutant mice recapitulate a range of neurological phenotypes seen in VS including biochemical deficits in autophagy, progressive motor dysfunction, and a strong molecular and cellular signature indicative of neuroinflammation. In parallel, we have established a novel engineered iPS cell-based platform for high throughput cell-based screens, which has identified rapamycin-related class of compounds (rapalogs) as enhancers of autophagy in the VS cells. This project will evaluate the therapeutic potential of the rapalog everolimus, an FDA-approved drug with over 14 years of safety data, including well-described use in pediatric populations, leveraging the VS mouse models for in vivo preclinical proof-of-principle studies. In Aim 1, we will define the pharmacokinetics (PK) and pharmacodynamics (PD) of everolimus in the VS mouse model, optimizing dosing regimens to sustain autophagy induction in vivo after extended use. In Aim 2, we will assess the ability of everolimus to slow or halt disease progression in vivo using the VS mouse model. Neurological function and inflammatory response in the VS animal model will be monitored during longitudinal treatment with everolimus. Phenotypic monitoring will include whole animal behavioral assays of motor function and molecular and histological biomarkers of neuroinflammation in various CNS tissues. Successful completion of this project will provide critical preclinical data supporting the repurposing of everolimus for clinical proof of concept in VS patients. Our multidisciplinary team, combining expertise in drug discovery, preclinical disease modeling and analysis in mice, clinical treatment of VS patients, and rare disease research, is well-positioned to advance this therapeutic strategy toward clinical translation in partnership with highly engaged VS families.

Up to $450K

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Assessment of Immune Responses to Neoantigen Vaccination in Lynch Syndrome

NCI - National Cancer Institute

PROJECT SUMMARY Lynch Syndrome (LS) is the most common cause of hereditary colorectal (CRC) and endometrial cancer (EC), affecting >1 million Americans. LS is caused by germline mutations in one of the four DNA mismatch repair (MMR) genes. Normal epithelial cells in LS carriers become MMR deficient after a ‘second’ somatic hit, thus triggering the accumulation of hundreds of insertion-deletion mutations (indels) in microsatellite sequences (i.e., microsatellite instability, MSI). These mutations generate frameshift peptides (FSPs) that act as neoantigens (neoAgs), which are recognized by T cell receptors (TCRs) for activation of the immune system. We posit that LS carriers constitute a well-defined and prevalent population that can maximally benefit from immuneinterception strategies with neoAg vaccines to prevent LS-associated carcinogenesis. We have acquired genomic and immunogenicity data from our institutional LS cohort to catalog the most frequently recurrent and shared mutated neoAg across the LS precancer to early-stage tumors as well as associated TCR clonotypes. Expansion of neoAg-specific TCR clonotypes and structurally similar TCR clones eliciting immune responses have not yet been studied in healthy, at-risk populations for cancer interception. Thus, the central hypothesis of this proposal is that specific TCR clonotypes against shared mutated neoAg reside in the colorectal mucosa as memory T cells and can be expanded after neoAg vaccination to elicit adaptive anti-tumor immunity. We have already completed an investigator-initiated, NCI-sponsored, multi-center Phase I clinical trial of an adenoviral vaccine (Nous-209) for prevention of LS-associated cancers. We recently reported the findings on safety and immunogenicity of Nous-209 vaccine which includes a total of 209 shared mutated neoAg covering a from MMRdeficient CRC, EC, and gastric tumors. Here, we propose the following three specific aims (SA): 1. To profile the T cell repertoire in the colonic mucosa of LS trial participants post-Nous-209 vaccination, and to match LS neoplasm-associated neoAg to specific T cell clones using machine-learning models; 2. To assess the spatial organization of neoAg-specific T cell clones in the colonic mucosal microenvironment pre- and post-vaccination using digital spatial transcriptomics and RNAscope; and 3. To assess neoAg-T cell reactivity ex vivo in LS organoid co-cultures and in vivo using murine tumor xenograft models. We are proposing to orthotopically implant a MMR-deficient CRC cell line model in animals to recreate the human tumor microenvironment, thus allowing us to examine the infiltration of immune cells into tumor, to assess the T cell response to tumor burden, and to characterize the mechanism of T cell-mediated activity in the tumor setting, which cannot be directly done in humans outside of a clinical trial. This proposal is highly innovative by combining single-cell genomics, spatial transcriptomics, and systems biology tools to assess the immune response to neoAg vaccination. This proposal will impact the field of hereditary gastrointestinal syndromes by developing a novel cancer prevention strategy for a population at high risk for different types of cancers, which may have implications for other cancer syndromes.

Up to $697K

2031-06-30

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Assessment of Reef Fish Populations within Dry Tortugas National

National Park Service

Dry Tortugas National Park represents a unique coral reef ecosystem that is isolated and contains a variety of reef fish habitats. This study will determine which habitats are important for hogfish and how and when hogfish utilize these habitats. Due to the high economic value of this species and recent regulation changes, understanding the temporal and spatial movement as well as the ontogenetic shifts in habitat use of hogfish are important for the management of this species. This study aims to provide managers with better information for the management, conservation, development, and restoration plan for this species.

$75K – $375K

Environmentalsustainability

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Assessment of Survival Rates of the Ipswich Sparrow

National Park Service

The goals of this project are to fill in the knowledge gaps of this migratory species of concern to better understand its overwintering habitat needs on a landscape level.

$1 – $45K

Environmentalsustainability

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Assessment of the contextual factors that influence implementation of a type 2 diabetes nutrition education curriculum in American Indian and Alaska Native-serving healthcare and community-based org

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY / ABSTRACT American Indian and Alaska Native (AI/AN) adults experience disproportionately high rates of type 2 diabetes (T2D) and face significant barriers to effective diabetes management. Group-based nutrition education has proven effective for improving nutrition self-efficacy, dietary behaviors, and glycemic management, but tailored programs for AI/AN communities are limited. In response, our team developed and pilot tested “What Can I Eat?” Healthy Choices for AI/ANs with T2D (WCIE) with support from the PI’s K01 (K01DK128023). WCIE is a tailored, 5-session, group-based diabetes nutrition curriculum supported by social cognitive theory. It includes emphasis on peer-to-peer discussions, traditional AI/AN foods, and the American Diabetes Association (ADA) diabetes plate method for meal planning. WCIE has demonstrated feasibility, acceptability, and early evidence of effectiveness. It has been endorsed by the ADA and disseminated via “Train the Trainer” workshops across 50+ AI/AN-serving organizations across the United States. However, preliminary feedback from trained WCIE educators reveals a critical implementation gap: challenges to delivering WCIE with fidelity. Examples of these challenges include: staffing, scheduling, and resource limitations. These modifiable barriers threaten the scalability and sustained impact of WCIE. To address this challenge, this R03 project enhances the PI’s K01 randomized controlled trial evaluation of WCIE by applying implementation science methods to systematically identify contextual determinants of WCIE delivery and co-develop feasible implementation strategies. Guided by the Consolidated Framework for Implementation Research (CFIR 2.0), Aim 1 will involve semi-structured interviews with 40–60 key informants from 20 AI/AN-serving health organizations to explore barriers and facilitators of WCIE implementation. Aim 2 will conduct implementation mapping using the CFIR-Expert Recommendations for Implementing Change (ERIC) tool, including focus groups and consensus-building with participants from Aim 1 to generate and prioritize a context-sensitive menu of implementation strategies. Deliverables include a refined implementation strategy menu and a step-by-step guide for applying the CFIR- ERIC mapping tool in partnership with AI/AN organizations. This work will directly inform a future hybrid effectiveness-implementation R01 trial. By improving fidelity to group nutrition education in diverse AI/AN contexts, this project addresses a critical gap in diabetes care, enhances community-driven implementation efforts, and strengthens the Early Stage Investigator’s career as a diabetes translation researcher. The study is innovative in its use of CFIR 2.0 with AI/AN-serving organizations and the inclusion of a rigorous, community- engaged implementation mapping process. Its impact extends beyond the WCIE curriculum, offering a replicable model for scaling culturally tailored interventions in resource-constrained settings. Findings will directly benefit health organizations serving AI/AN populations by improving T2D outcomes through more sustainable, context- aware program delivery.

Up to $120K

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Assessment of the current condition and future vulnerability of sugar pine in the Sierra Nevada: Evaluating the drivers of change in a declining species

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of the NPS' intention to fund the following project activities without full and open competition: Cooperative Agreement P19AC01249 with the Regents of the University of California, Berkeley, a partner under the Californian Cooperative Ecosystem Studies Unit (Cooperative and Joint Venture Agreement NPS-CALI-CESU-2018), for the project titled, "Assessment of the current condition and future vulnerability of sugar pine in the Sierra Nevada: Evaluating the drivers of change in a declining species."

$30K – $60K

natural resources

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Assessment of thymic output in the context of genetics, environmental exposures, and progression to type 1 diabetes

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Type 1 Diabetes is rising in incidence and is most commonly diagnosed before the age of 10, predisposing patients to lifelong complications. The window for intervention is narrowing as the overall mean age at diagnosis is decreasing with time. Although we can identify genetic risk for T1D using polygenic risk scores, disease prevalence among those without known genetic risk is also increasing over time, suggesting that environmental factors may contribute to the autoimmune process. Our current understanding of the involvement and interplay of genetics and environment has relied on intensive population screening efforts, including The Environmental Determinants of Diabetes in the Young (TEDDY) study supported by the NIH. The major inflection point for T1D disease progression is seroconversion (development of autoantibody positivity). Though valuable in prediction, these tests are not administered in pediatric clinics. Population level screening for this relatively low-occurrence event is laborious and costly, as time from seroconversion to disease development can range from months to years, depending on genetics, age at seroconversion, the specificity of the first-appearing autoantibody, as well as the autoantibody titer. Decades of research support autoantibodies as predictive tools for estimating likelihood of T1D over time, yet the field still lacks understanding of the early initiating events pushing T cells to enact pancreatic beta cell loss. We have defined key features of accelerated immune aging in T1D via flow cytometry. However, although peripheral T cell phenotype and function have been extensively studied in T1D, it remains unclear how thymic function is impacted during the progression to diabetes. The thymus is exquisitely responsive to environmental stimuli, including stress, nutritional changes, viral infection and inflammation, all noted as major contributors to T1D. We hypothesize that the observation of accelerated aging and exhaustion in T1D is reflective of a smaller, inflammatory- skewed naïve T cell pool, reduced thymic output, and peripheral expansion of memory T cells in response to environmental insults. This provides an opportunity for a T cell-specific biomarker of disease progression. The objective of this proposal is to inform on peripheral T cell phenotype and thymic output as a function of age, environmental exposures and risk for T1D. This approach emphasizes sample sparing assays and novel analysis of existing data. We expect that this project will provide robust biomolecular signatures, producing a novel, clinically relevant biomarker in the pathogenesis of T1D.

Up to $154K

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Assessment of Water Quality Conditions in and around Four Pacific Northwest Coastal Parks

National Park Service

United State Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of NPS' intention to fund the following project activities without full and open competition: Task Agreement P14AC01693 under Cooperative Agreement H8W07110001 with the University of Washington, a partner under the Pacific Northwest Cooperative Ecosystem Studies Unit, for the project titled, "Assessment of Water Quality Conditions in and around Four Pacific Northwest Coastal Parks."