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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Functional dyspepsia (FD) is common, affecting 12% of adults in the United States with high morbidity (e.g., work absenteeism, malnutrition) and healthcare costs. FD symptoms most commonly include early satiation and epigastric pain, worsened by meal ingestion in the absence of clear structural etiology. Precision medicine is lacking due to the complex pathophysiology thought to underlie gut-brain axis dysfunction in FD. Identification of maintenance mechanisms is necessary to determine which existing and new treatments work for whom and why. Gut interoception—how the gut and brain communicate to sense (i.e., attend to), interpret, and integrate gut signals at both conscious and unconscious levels—may be a useful model for understanding dynamic body-to-brain (‘bottom up’) and brain-to-body (‘top down’) processing in FD. This proposal uses multi- disciplinary methods (i.e., functional magnetic resonance imaging: fMRI, resting state functional connectivity, gut connectivity, self-report). We will examine three dimensions of interoceptive processing: gastric attention, interpretation of gastric signals, and gut-brain signal integration. We will contrast gut interoception in adults with FD (n=50) to healthy controls (n=50) and a clinically relevant comparator (anorexia nervosa; n=50) to test our central hypothesis: FD is linked to neural hyper-attention to gastric signals, neural fear-based interpretation of gastric signals, and poor bi-directional gut-brain integration. First, we hypothesize FD will exhibit fasting and pre-meal neural hyper-attention to gastric cues in primary interoceptive regions (insula, anterior cingulate cortex) of the Salience Network (involved in interoception and cognitive/emotional integration). We expect hyperactivation to correlate with a trait-level gut interoceptive awareness. Second, we hypothesize that FD will show pre-and post-meal resting state hyperconnectivity in the primary hub of interoception—the mid insula— and the amygdala (primary limbic region of the Salience Network) alongside hypoconnectivity with the orbital frontal cortex (a primary food-reward region of the Salience Network). Finally, we expect FD to show greater connectivity than controls and AN between the nucleus tractus solitarius (key brain stem region involved in processing interoceptive signals) and the Salience Network, which we expect will correlate with slower gastric motility. Conceptualizing FD pathophysiology within an interoceptive framework has strong potential to advance precision medicine for FD by identifying neural mechanistic targets—hyper-attention (e.g., attention re-training), dysregulated interpretation (e.g., behavioral exposure therapy), and altered integration (e.g., vagal nerve stimulation).

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Vector-borne diseases such as malaria cause approximately 700,000 deaths each year. To support insect vector control, pyrethroid insecticides are widely deployed. However, the rise of resistance has reduced their effectiveness, prompting the use of combination treatments that pair pyrethroids with chlorfenapyr—an insecticide with a distinct mode of action. Evidence suggests that specific pyrethroid resistance alleles can modulate responses to chlorfenapyr, potentially driving synergistic effects when the two insecticides are combined. This interaction raises concern that similar or novel gene-by-treatment interactions could also influence human responses, complicating chemical risk assessment for genetically diverse human populations. The overall objective of this proposal is to integrate low-cost, high-throughput quantitative genetics in C. elegans with human cell culture to investigate the genes and molecular pathways that influence responses to insecticides alone and in combination. The rationale for the proposed research is that identifying the conserved genes and molecular pathways that harbor natural variants influencing responses to combined insecticide exposure can help inform risk assessment for humans. In Aim 1, we will map quantitative trait loci (QTL) that influence responses to chlorfenapyr and four pyrethroids, both individually and in combination, using wild strains and recombinant inbred lines of C. elegans. In Aim 2, we will identify specific genes and variants within QTL that cause differences in insecticide responses using experimental crosses and CRISPR/Cas9 genome-editing. In Aim 3, we will profile transcriptomic responses to insecticides in C. elegans strains with causal edits and in human HEK293 and HepG2 cells to identify conserved pathways associated with responses to combined insecticide exposure. The innovation of this proposal stems from the integration of high-throughput quantitative genetics in C. elegans with cross-species comparative transcriptomics. This approach has never been used to investigate the effects of natural variation on combined insecticide susceptibility. The proposed research is significant because it will uncover molecular mechanisms underlying natural variation in susceptibility to combined pyrethroid and chlorfenapyr exposures, and identify candidate genes that may harbor susceptibility alleles relevant to human populations. Importantly, this proposal aligns with the objectives of the AREA R15 mechanism by (1) increasing undergraduate involvement in toxicology and genetics research, and (2) strengthening the research infrastructure at the Florida Institute of Technology.

IEEE Foundation

Supports STEM education, technology literacy, and engineering innovation programs that advance technology for humanity.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract The IL-17 family of cytokines is extensively studied and plays a crucial role in immunity and inflammation. While anti-IL-17A or anti-IL-17RA therapies are commonly used to treat patients with plaque psoriasis, they have been unsuccessful in treating inflammatory bowel disease (IBD) and, in some cases, have even worsened the condition. There have also been reports of new-onset IBD in individuals receiving IL-17A-neutralizing therapies. Additionally, the colonic epithelium of IBD patients often accumulates mutations that affect IL-17A signaling. These findings, counterintuitively, suggest that IL-17A responses in the gut may be beneficial. Published studies have shown that IL-17A responses in intestinal epithelial cells are critical for maintaining gut barrier integrity, supporting intestinal Th17 immune responses, regulating epithelial redox balance (via Nox1-H₂O₂), and controlling colonization by segmented filamentous bacteria (SFB). However, there remains a significant gap in understanding of the molecular mechanisms through which IL-17A promotes mucosal host defense. In addition to the epithelium and Lgr5+ intestinal stem cells (ISCs), certain intestinal mesenchymal stromal cell subsets— such as telocytes and trophocytes—also express the IL-17A receptor complex (IL-17RA/IL-17RC). At present, little is known about the role of IL-17A in these stromal subsets. Preliminary studies have identified a previously unreported function of IL-17A in activating stromal cells to induce a fetal-like reprogramming of epithelial cells. The central hypothesis of this proposal is that IL-17RA signaling in stromal cells is essential for epithelial regeneration. Aim 1 will define IL-17A-dependent regulatory pathways in specific intestinal stromal cell subsets. Aim 2 will investigate how stromal cell function supports epithelial regeneration. Aim 3 will explore stromal cell induced epithelial regeneration pathway in IBD. Impaired intestinal epithelial regeneration is a hallmark of IBD. The successful completion of these studies will have broad implications for a range of diseases, both within and beyond the gut, in which tissue regeneration is compromised.

Illinois State Board of Education

STEM education initiative grants for IL to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

ITW Foundation

Supports workforce development, STEM education, and community programs in ITW communities worldwide.

National Institutes of Health

The National Institute on Aging (NIA) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications that propose a program that supports integrative, cross-disciplinary projects aimed at scaling up mechanistic studies to understand the genomic underpinnings of the pathogenesis and progression AD/ADRD.The proposed research projects will employ interdisciplinary approaches that integrate innovative techniques to dissect the genomic drivers of AD/ADRD. These projects will leverage advanced analytical methods, including machine learning and comparative genomic analysis across multiple genetic ancestries or multiple neurodegenerative diseases, along with cutting-edge tools like genome editing, functional characterization assays, and emerging single-cell and spatial omics technologies. These studies will use sophisticated disease models, such as human stem cell-based systems, ex vivo, and in vivo models that reflect different genetic ancestries, various model organisms, or multiple neurodegenerative conditions. These cross-ancestry, cross-disease, and cross-species approaches will enable a more comprehensive investigation of the genomic drivers of neurodegeneration and neuropathogenesis. Ultimately, this initiative may lead to the identification of actionable therapeutic targets for AD/ADRD, meeting the urgent need for mechanism-driven insights that can guide precision medicine approaches for its treatment.Applications are not being solicited at this time. This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO intends to utilize the U01 activity code. Investigators with expertise and insights into this area of aging research are encouraged to begin to consider applying for this new NOFO.

National Institutes of Health

<p style="margin-left:0in;">The National Institute on Aging (NIA) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications that propose a program that supports integrative, cross-disciplinary projects aimed at scaling up mechanistic studies to understand the genomic underpinnings of the pathogenesis and progression AD/ADRD.</p><p>The proposed research projects will employ interdisciplinary approaches that integrate innovative techniques to dissect the genomic drivers of AD/ADRD. These projects will leverage advanced analytical methods, including machine learning and comparative genomic analysis across multiple genetic ancestries or multiple neurodegenerative diseases, along with cutting-edge tools like genome editing, functional characterization assays, and emerging single-cell and spatial omics technologies. These studies will use sophisticated disease models, such as human stem cell-based systems, ex vivo, and in vivo models that reflect different genetic ancestries, various model organisms, or multiple neurodegenerative conditions. These cross-ancestry, cross-disease, and cross-species approaches will enable a more comprehensive investigation of the genomic drivers of neurodegeneration and neuropathogenesis. Ultimately, this initiative may lead to the identification of actionable therapeutic targets for AD/ADRD, meeting the urgent need for mechanism-driven insights that can guide precision medicine approaches for its treatment.</p><p style="margin-left:0in;">Applications are not being solicited at this time. This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.&nbsp;This NOFO intends to utilize the U01 activity code. Investigators with expertise and insights into this area of aging research are encouraged to begin to consider applying for this new NOFO.</p>

NIAID - National Institute of Allergy and Infectious Diseases

Abstract: Decades of research on transplantation have made it clear that the immunological barriers to engraftment are substantial. The goal of this proposal is to generate transgenic mouse models that will allow standardized and orthogonal testing of pathways important for overcoming transplantation barriers, and through this work, instruct efforts in regenerative medicine. We will generate mice that, upon Cre recombinase expression, will express modules of genes that either 1) suppress complement deposition and membrane attack complex formation; 2) express single chain peptide-β2m-MHC trimers to engage inhibitory receptors on natural killer cells; 3) express CD47 to engage the inhibitory receptor Sirpα. These animals can be used as donors for future transplantation experiments to genetically define allogeneic barriers and instruct similar edits in stem cells for regenerative medicine.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Advances in cancer treatment have led to longer survival, making late cardiovascular complications a growing concern in survivorship care. One newly recognized contributor to heart disease in cancer patients is clonal hematopoiesis of indeterminate potential (CHIP), a clonal expansion of hematopoietic stem cells due to acquired somatic mutations. CHIP has been associated with elevated risks of cardiovascular diseases (CVD) and higher all-cause mortality, independent of traditional cardiovascular risk factors. While genotoxic cancer therapies such as radiotherapy and chemotherapy have been implicated in CHIP pathogenesis, the prevalence of therapy-related CHIP and its impact on cardiovascular outcomes remain severely understudied. Furthermore, there are currently no clinical guidelines for screening CHIP in cancer patients, nor validated tools to stratify CVD risk in individuals with CHIP. The proposed study will directly address these unmet needs by defining the relationship between cancer therapies and CHIP development, evaluating the impact of therapy-related CHIP on CVD outcomes, and developing a CVD risk stratification tool tailored for cancer survivors. The research proposal leverages our Vanderbilt BioVU DNA biobank which has recently completed whole genome sequencing of >250,000 patients, including >78,000 cancer patients. The proposal consists of three aims: 1) to identify the prevalence and risk factors for CHIP in cancer patients; 2) to define and predict the impact of CHIP on CVD risk; and 3) to track the longitudinal clonal dynamics of therapy-related CHIP. Successful completion of these aims will lay the groundwork for a precision survivorship model that integrates CHIP status into a comprehensive cardiovascular risk assessment, more personalized cancer treatment strategies, and future interventional trials designed to reduce long-term CVD risk in this growing patient population. Dr. Leo Luo is a radiation oncologist and physician-scientist at Vanderbilt University Medical Center (VUMC). His research and career development will be conducted at VUMC, which offers a rich and collaborative research environment, extensive sources for early-career investigators, and an outstanding track record of successful mentorship. In addition to his primary mentor, Dr. Luo has established a research advisory committee composed of internationally recognized experts in CHIP, cardiovascular research, and bioinformatics. His structured training plan in cardio-oncology, genomic analysis, and epidemiology will develop the skills necessary for him to pursue a research program that is distinct from that of his mentors and facilitate his transition to an independent, R01-funded physician-scientist.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Myelodysplastic syndromes (MDS) are clonal, age-related bone marrow failure disorders that affect aged individuals and are met with limited treatment options, despite high rates of mortality. Mutations in ten-eleven translocation protein 2 (TET2) drive disease in MDS and associate with poor prognosis. However, some individuals with no hematopoietic disorder harbor these mutations and have low probability of progression to disease. It is unknown why some patients with TET2 loss have disease while others will not. Innate immune inflammation elicited by bacterial products drives clonal expansion and disease progression in TET2-deficient mouse models. Yet it is not understood how innate immune inflammation interacts with TET2 loss during physiological challenges throughout an individual’s lifetime, hindering development of therapies. Receptor interacting serine/threonine kinase 1 (RIPK1) plays a central role in inflammatory signaling pathways such as TLR4 signaling, and inactivation of its kinase activity alleviates some of the inflammatory repercussions of TET2 loss, revealing a potential therapeutic target. TET2 loss also impairs effective innate immune cell function and augments inflammation following bacterial infection. In WT mice, prior MPLA exposure (a toll like receptor 4 (TLR4) agonist known to initiate innate memory) improves innate immune function and dampens inflammation during subsequent bacterial infection. The objective of this proposal is to apply the powerful model of innate immune memory to TET2 deficiency and define how infection and incomplete inflammatory resolution promote disease progression. Due to the inflammatory nature of TET2 loss, I hypothesize that inflammation initiated by MPLA with infection persists, promoting disease progression. Additionally, I expect RIPK1 augments inflammation in TET2 loss, playing an essential role in disease progression. To explore these hypotheses, I will apply MPLA-induced innate immune memory to murine models of TET2 deficiency and RIPK1 inactivation, which is unique in its ability to augment pathogen clearance while simultaneously dampening inflammation. Aim 1 will utilize a slowly progressive S. aureus infection model to define innate immune cell function deficits, incomplete inflammatory resolution, and hematopoietic dysregulation in TET2 loss and the function of RIPK1 in moderating these effects. Aim 2 will then elucidate how inflammation and disease progression are altered in TET2 loss by examining differentiation and inflammatory signaling in vitro under MPLA stimulation, following which I will stimulate mice in vivo with different TLR agonists prior to infection to determine the mechanism of hematopoietic dysregulation. These Aims will collectively define how infection-induced inflammation promotes disease progression in TET2 loss, thus promoting our understanding of the biology of clonal expansion in hematologic disease in a physiologically-relevant setting. The results of these studies will have broad translational applicability to advancing treatment options for patients affected with MDS to specifically target inflammatory pathways, which minimize disease progression and improve patient outcomes.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY Micro- and nanoplastics (MNPs) are emerging as a ubiquitous and persistent environmental contaminant. Human exposure to MNPs is widespread, with ingestion being the main exposure route. Research addressing the potential impact of MNPs on human health is urgently needed. MNPs can reach and accumulate in the heart. However, the impact of MNPs on the heart is very poorly understood. Notably, a recent epidemiologic study has shown that higher exposure to MNPs is associated with increased cardiovascular events in human patients. This new evidence highlights the potential cardiovascular toxicity of MNPs in humans and the critical need to understand the effects of MNPs exposure on the heart. In preliminary studies in human inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and/or rats, we found that exposure to MNPs caused cardiac toxicity including reduced cardiac myocyte viability, increased reactive oxygen species (ROS), and decreased left ventricular mass. Remarkably, in rat exposure studies, we found that MPNs exposure significantly increased myocardial infarction size and cardiac tissue damage following cardiac ischemia injury. Supported by compelling preliminary results, we propose to address the central hypothesis that exposure to environmental MNPs causes mitochondrial dysfunction and oxidative stress in the heart, leading to increased susceptibility of the heart to damage; such cardiac toxicity is manifested as worsened infarction and heart dysfunction following ischemia injury (ie, heart attack). The proposed study will be carried out by an interdisciplinary team that comprises researchers in cardiac toxicology, chemistry, clinical cardiology, and biostatistics. The study uses both an in vivo rat model and human iPSC-derived cardiomyocytes and human cardiac organoid models, and are of strong relevance to human heart health. Importantly, taking advantage of our breakthroughs in producing “true-to-life” MNPs that mimic real-life environmental MNPs, we will use such “true-to-life” MNPs in the entire study, making the study highly relevant to real-life environmental MNPs exposure. In whole animal exposure studies, internal MNPs exposure levels and tissue distribution will be analyzed using state-of-the-art analytical chemistry approaches. Three aims are proposed. Aim 1 examines the impact of MNPs on cardiac physiology and function; Aim 2 addresses the impact of MNPs on cardiac damage and adverse outcomes following ischemia injury; Aim 3 examines the mechanism underlying MNPs-induced cardiac toxicity, focusing on the autophagy-lysosome pathway and mitochondria dysfunction. The proposed studies are significant because they are expected to provide critical knowledge on MNPs-induced cardiac toxicity in human-relevant experimental models, thus having strong environmental health significance. Further, the studies will contribute to our recognition of the role of MNPs in affecting the outcomes of heart attack - a top cause of death and morbidity in the US, thus having strong clinical and translational impact.

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Epidemiological evidence links peripheral inflammation to an increased risk of dementia, yet the mechanisms underlying this association remain unclear. Although peripheral immune challenges can amplify neuroinflammation and accelerate cognitive decline, we still do not understand the thresholds required to elicit neuroinflammatory responses that alter neuronal activity, their underlying cellular mechanisms, or how these thresholds and mechanisms change with age. This gap stems from viewing neurons as a passive recipient of neuroinflammatory signals, but also from the use of models with limited relevance. Our long-term goal is to understand how peripheral inflammation interacts with aging to increase the risk of dementia. Prior studies showed that aging sensitizes microglia, making them highly responsive to immune signals and driving exaggerated responses that disrupt synaptic circuits and lead to cognitive deficits. Furthermore, increasing evidence-including our preliminary data-indicates that peripheral inflammation can also directly alter neuronal activity and connectivity. Our proposal builds on this foundation and advances a novel hypothesis: while chronic inflammation directly activates microglia, in acute inflammation, the flow of events begins with neurons. Our preliminary data show that acute inflammation initially alters the activity of inhibitory neurons in key cortical regions. This change may then be detected by microglia, which respond according to their current, age-dependent state by further altering inhibitory synapses and the excitation-inhibition balance. To test this hypothesis, we will use mouse models that mimic common human inflammatory conditions: house dust mite (HDM}-induced respiratory allergy and dextran sulfate sodium (DSS}-induced colitis. Aim 1 will define microglia responses to acute and chronic inflammation as a function of age and will assess whether T cells contribute to increased responses of microglia to acute inflammation in aged mice. Aim 2 will test whether changes in inhibitory activity following acute inflammation trigger microglia activation in aged mice and will define the associated microglial molecular responses. Aim 3 will examine if microglia respond to changes in inhibitory activity by further altering cortical circuits in an age-specific manner. With expertise in molecular, cellular, and circuit neuroscience, inflammation, and imaging, our team is uniquely positioned to carry out this interdisciplinary project. The Pl's past discovery of specific microglia-inhibitory neuron interactions is an additional strength. We will use an innovative approach that combines relevant mouse models, advanced immunological techniques (e.g., adoptive transfer, immune cell depletion), and state-of-the-art neuroscience methods (e.g., calcium imaging, chemogenetics) to test our hypothesis. This research addresses a significant biomedical challenge-understanding how peripheral inflammation affects the aging brain-and has the potential to transform our understanding of neuroimmune interactions in dementia. We will identify key features of microglia-PV neuron interactions following peripheral inflammation and define how they shift with aging. Ultimately, our findings could reveal age-specific therapeutic strategies to reduce the risk of dementia.

NIAID - National Institute of Allergy and Infectious Diseases

Accidental or deliberate radiation exposure of humans remains a major health concern, due to the paucity of medical countermeasures (MCMs) to ameliorate radiation-induced damage. While high dose radiation exposure is generally fatal, even low dose whole body (WBI) or partial radiation exposure can have acute- and/or delayed- negative impacts that appear to act through disruption of the immune system. The cytoreductive effects of WBI have long been exploited in conjunction with chemotherapy as a preparative regimen prior to hematopoietic stem cell transplant in patients with blood cancer to deplete malignant cells and suppress the immune system. While there is strong evidence that radiation kills rapidly dividing cells, a hallmark of the immune system, and induces inflammation that can mediate tissue destruction, the precise nature of radiation induced immune-dysfunction is not well understood. This knowledge gap is a key impediment to development of MCMs to treat radiation exposure. For one example, memory CD8 T cells provide enhanced resistance to re-infection and malignancies. However, most studies in the literature examine the impact of radiation exposure on the capacity of the host’s naïve CD8 T cells to mount a new (primary) immune response and just a few reports have looked at how radiation exposure influences the longevity and protective capacity of pre-existing pathogen or vaccine-induced CD8 T cell memory. Memory CD8 T cell populations have the job of surveying the entire body for signs of re-infection. They accomplish this task using two complimentary and interactive strategies. This first strategy involves populations of memory CD8 T cells that survey the body by using the circulatory system (circulating memory CD8 T cells - Tcircm). The second strategy involves the generation of a population of non-circulating memory CD8 T cells (called T resident memory, Trm), generally in the tissue of pathogen entry. These cells, which persist long-term in tissues, provide rapid detection of re-invading pathogens and then send out mediators to recruit other cells of the immune system to the site of infection. Importantly, our recent data obtained after WBI or partial (targeted) thorax radiation suggest that sublethal ionizing radiation inflicted numerical and functional damage to Tcircm and Trm cells that diminished their ability to provide protection to pathogen-re-encounter. Our long-term goal is to precisely identify mechanisms that govern maintenance, differentiation and function of infection and/or vaccine- induced memory CD8 T cell subsets and explore modalities to recover memory CD8 T cell responses in radiation survivors. We will address our long-term goal through the following specific aims: SA1 - Delineate the tissue-specific impact of WBI on pathogen-specific Trm and evaluate targeted vaccine strategies to restore memory CD8 T cell numbers and function after irradiation. SA 2 - Define mechanisms underlying WBI-induced numerical and functional diminishment of Tcircm and exhausted (Tex) CD8 T cells generated after acute or chronic viral infections.

Imperial Oil

Supports STEM education, Indigenous community development, and environmental programs across Canada.

NCI - National Cancer Institute

PROJECT SUMMARY Our overall objective is to identify the best strategies for lung cancer screening (LCS) in a representative group of people with HIV (PWH). Lung cancer (LC) is now the leading source of cancer mortality among PWH. Unfortunately, most LCs in PWH are diagnosed at a late stage and have very poor survival. Thus, LCS among PWH is needed to stem this growing source of preventable mortality. Two large trials demonstrated that LCS with low-dose chest computed tomography (LDCT) reduced LC mortality among heavy smokers without HIV (PWoH). We have confirmed the benefits of LCS in well-controlled PWH who have a high-risk smoking history and guidelines recommend LCS for PWH. Many issues regarding the optimal indications for LCS in PWH remain unclear, however. Research in PWoH has shown that LC risk prediction models, such as the PLCOm2012 score, are superior to current eligibility criteria for LCS. PWH develop LC with less tobacco exposure and at earlier ages and existing LC risk models have not been developed or tested in PWH, a population for which several unique LC risk factors (e.g., low CD4/CD8 ratio values) exist. Additionally, false positive lung nodules are common in LCS. Robust algorithms to work-up these nodules are critical to minimize the harms of LCS. However, current nodule follow-up protocols do not consider several important factors affecting PWH like an increased rate of false positive screens, follow-up testing complications and competing risks of death. While LCS is recommended for PWH with well-controlled HIV, several other factors such as increased comorbidities and other HIV-related factors that affect life expectancy and quality of life may impact the optimal regimen for LCS in PWH. Therefore, the VACS index, a validated HIV mortality risk index, may be a convenient tool for further improving the screening decision-making process. Our overall goal is to use simulation modeling to improve LCS regimens for PWH. Our Aims are to: 1) Derive and validate an HIV- specific LC risk prediction model; 2) Compare the impact of LCS eligibility criteria based on USPSTF guidelines, existing risk prediction models for PWoH, and a novel HIV-specific LC risk prediction model on LC mortality reduction in PWH; 3) Identify optimal recommendations for management of screen-detected nodules in PWH; and 4) Determine personalized indications and LCS regimens according to HIV-related prognosis (based on the VACS index) and major comorbidities common among PWH (chronic obstructive pulmonary disease, cardiovascular disease and liver disease) that maximize benefits and minimize harms. In Aim 1, we will apply machine learning methods to data from several of the largest US HIV cohorts to derive and validate an HIV-specific LC risk prediction model. For Aims 2 to 4, we will update and use a well-established simulation modeling framework previously developed by our group. Using the updated model, we will evaluate the best criteria for eligibility for LDCT screening in PWH, identify the most effective strategies to work-up screen- detected nodules and assess personalized LCS indications that consider HIV-related prognosis.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT Mild traumatic brain injury (mTBI) or “concussive” injuries are a major societal issue and are associated with activities such as sports, motor vehicle crashes, and falls. Sports-related concussions in children and adolescents (5-18 years) account for between 30-60% of all pediatric concussions. There currently exists no available technology to provide accurate measurement of head impacts in concussive or sub-concussive environments. While a number of head impact exposure devices are on the market or are in development, few of these devices have undergone baseline validation studies to assess the accuracy of their results in biofidelic environments. When events are detected using these systems, there is little support as to whether the data is of a relevant impact or spurious in nature when device deployment is unsupervised. Most existing systems rely on simple acceleration thresholds as a trigger to begin data collection. While such methods are easy to implement and interpret, the trade-off is collection of spurious events above the threshold, and loss of data for events below the threshold. We propose utilizing the Data Acquisition System for Head Response (DASHR) to better understand patterns in head kinematic behaviors leading to and characteristic of head impact in youth football as a mechanism by which relevant and spurious wearable sensor data can be distinguished. We propose leveraging existing DASHR head impact exposure data and video data from prior seasons in concert with prospective data acquired from the DASHR in two upcoming seasons alongside newly acquired high-definition video data. This study benefits from extensive leveraging of existing work stemming from an on-going longitudinal study that the investigators and community collaborators are already engaged in, allowing for additional resources to be devoted to high-definition video acquisition coupled with an overall reduction in the total-price point for comparable studies due to the existing and parallel data sources. These data will be utilized to develop and assess post-processing algorithms using machine learning methods to develop an improved data acquisition pipeline for the DASHR and similar systems more accurately distinguishing relevant impacts from non-relevant events. DASHR data and auxiliary sensor input from the prior four years and the first prospective year will be utilized to train (learning dataset) for the algorithm. Year two of the prospective study will be utilized as a validation dataset to assess the effectiveness of the post-processing algorithm on correctly identifying relevant and non-relevant head impact exposure. The proposed study would be the first to design and develop an algorithm capable of effectively identifying relevant impacts from continuous time-series head kinematic data, using pre-impact behavioral patterns and impact characteristics, with video data as ground truth for validation and assessment.

NIH

Significance to VA: There are few treatment options for Veterans with spinal cord injuries (SCI). Recently the Tuszynski lab has developed an approach where neuronal stem cells are implanted into the injury site. These grafted cells differentiate into neurons which extend axons caudally to form synapses with the host; simultaneously, host axons enter the graft and form synapses with graft neurons. This system restores connectivity across the lesion site and improves functional recovery in rodent and primate models. However, recovery is incomplete, in part because of only partial growth of host axons into and within the graft. Innovation and Impact: This CDA-1 proposal will use a new path to enhance the graft by exploiting the existing biology of the graft to enhance its functionality. Specifically, it will explore the role of axonal guidance cues (secreted molecules that attract or repel growing axons) in the graft and manipulate these cues to increase host axon growth into the graft and improve connectivity across the injury site. The Tuszynski lab is currently beginning the process of clinical implementation of our graft system. Success in this project and follow-up work in a CDA-2 award will lead to approaches which can be used to improve the functionality of grafts to improve recovery for SCI patients including Veterans. Specific Aims: This proposal will test the hypothesis that a mismatch of secreted guidance cues may limit host axon regeneration into the graft. This proposal will target mechanisms associated with axon growth into stem cell grafts and test whether modifying guidance cues will increase host axon regeneration into the graft. Aim 1 will focus on reducing the inhibitory effects of the injury site. Injury sites express Wnts which inhibit the growth of corticospinal tract (CST) axons via binding to the Ryk receptor. This aim will test the hypothesis that neutralization of the inhibitory effect of Wnts will increase CST axon growth into the graft. Aim 2 will focus on increasing the attractive environment of the graft. Axons that enter the graft grow towards appropriate interneuronal targets, indicating that some attractive cue exists; however, the relatively short distance of growth within the graft (1-2 mm) suggests that the effects of this cue are limited. A viral labeling and sequencing approach will be used to identify and validate these attractive cues released by the graft. Methodology: Both Aims will be performed in mice using a C4 contusion model of spinal cord injury. Regeneration of host CST axons into the graft will be assessed with histology (N=12 per group). Functional recovery following SCI will be assessed with behavioral performance on a skilled reaching task (N=30 per group). Treated animals will be compared to our current grafting paradigm to determine if these treatments improve the efficacy of the graft in recovery following SCI. Path to Translation/Implementation: Treatments for spinal cord injury are currently limited, and success of this proposal may increase the effectiveness and therapeutic potential of stem cell grafts. While work in this proposal is limited to mouse grafts, future work in a CDA-2 award would test any treatments identified here in human cell grafts which could then be implemented as part of a clinical product to treat Veterans with SCI. The proposed project will provide excellent research training for the applicant including systems neuroscience, spinal cord injury, and human disease. Additionally, he will learn multiple techniques including rodent models of SCI, mouse behavioral assessment, and RNA sequencing. The research environment of the Tuszynski lab is highly collaborative so he will gain exposure to many techniques and subject areas beyond his own research, refine his scientific presentation skills, mentor younger scientists, and network with leaders in the field. Finally, he will directly engage with Veterans by shadowing doctors at the VA San Diego Medical Center while they treat Veterans recovering from SCI. Overall, this CDA-1 grant will provide new insight into novel therapeutic avenues for spinal cord repair and allow the applicant to transition into a career as an independent investigator at the VA.

NIH

Rotator cuff tearing, a pervasive age-related shoulder injury, imposes a substantial burden on millions of patients in the United States, particularly within our aging Veteran population. Up to 20% of individuals over 50 exhibit symptomatic rotator cuff tears, and nearly half of those aged 70 or older are grappling with this condition. Shoulder pain and dysfunction emerge as the major symptoms for patients with rotator cuff tears. While non-surgical treatments prove effective for smaller tears, the management of larger or massive rotator cuff tears demands surgical repair. Poor muscle quality stands out as a critical contributor to the failure of rotator cuff tendon repairs, emphasizing the pivotal role of enhancing muscle quality for advancing clinical outcomes in patients with rotator cuff repairs. In the past decade, our laboratory has been at the forefront of unraveling the complexities of rotator cuff muscle degeneration and regeneration. Our groundbreaking studies have elucidated the role of muscle stem cells, specifically fibro/adipogenic progenitors (FAPs), in this context. Notably, our findings in both mice and humans have demonstrated the transformative potential of inducing FAP brown/beige fat (BAT) differentiation and horizontal mitochondria transfer toward myocytes. These mechanisms effectively reduce muscle degeneration and promote shoulder function post-rotator cuff tears. Though the detailed mechanism remains unknown, blood flow restriction (BFR) therapy, a method that temporarily limits blood flow in limbs, emerges as a promising intervention in reducing muscle atrophy and musculoskeletal pain. Our recent endeavors to unlock this mystery have uncovered the potential benefits of BFR in stimulating FAP BAT differentiation and horizontal mitochondria transfer during muscle regeneration. Adding to our arsenal of innovation, we've developed a low-cost tool employing machine learning techniques to quantitatively assess shoulder function. This tool, analyzing hand-over-hand string-pulling motions, provides a reliable means of evaluating shoulder health in both animal models and human subjects with rotator cuff tears. Additionally, our novel machine-learning approach utilizes the Blackbox® system to measure mechanical pain in mice following rotator cuff tears, offering a nuanced understanding of pain dynamics. Looking ahead, our proposed study aims to push the boundaries of innovation further. In this proposed study, we aim to define the role of BFR in a preclinical rotator cuff tears and repair model to evaluate the effectiveness of BFR in stimulating FAP BAT differentiation and mitochondria transfer, reducing muscle atrophy and degeneration, enhancing shoulder function, and alleviating pain. This groundbreaking research aligns with our vision of translating innovative findings from the laboratory to future clinical trials, promising impactful outcomes for patients with rotator cuff tears, particularly within the aging veteran population.

NIH

Significance to VA: Every year, nearly 2 million Veterans undergo prostate-specific antigen (PSA) screening for prostate cancer within VHA. Despite widespread use, current screening practices are inconsistent and inefficient, leading to unnecessary biopsies, overtreatment, and missed opportunities for early intervention. These inefficiencies stem from the uncoordinated nature of the screening care cascade—a series of complex, multistep decisions involving screening timing, follow-up imaging, biopsies, and treatment choices. Prior attempts to improve PSA screening in VHA have focused on isolated steps within the cascade, missing critical interdependencies and failing to identify where improvement is most needed. To optimize outcomes, a comprehensive understanding of the entire care cascade is essential. One promising alternative approach is microsimulation, which simulates millions of patients as they undergo screening, diagnosis, and treatment for prostate cancer (i.e., the entire care cascade), allowing analysis of complex care decisions in an integrated, system-wide context. This approach is widely used to inform national cancer screening guidelines for this very reason. The overall objective of this proposal is to develop a VHA-specific microsimulation model of prostate cancer care, enabling rigorous identification of potential improvement opportunities, development of high-impact strategies tailored to VHA, and a detailed accounting of benefits and harms. This work is significant because it would be an enormous leap forward in VHA's ability to identify, analyze, and address opportunities to improve complex, multi-step cancer care pathways through microsimulation. This would result in a methodological toolbox that could be applied to other cancer care pathways and produce concrete benefits for the millions of Veterans undergoing PSA screening each year. Innovation and Impact: The research in this CDA is innovative because it would be the first use of microsimulation to identify opportunities for improvement in a VHA cancer care pathway and develop evidence- backed strategies to address them. This work has the potential to revolutionize how VHA develops and prioritizes cancer screening quality improvement initiatives by enabling VHA to identify the highest-impact strategies and allocate scarce resources accordingly. Specific Aims: Aim 1: Describe facility-level variation and potential improvement opportunities in PSA screening care cascades. Aim 2: Adapt an established microsimulation model to reflect current VHA prostate cancer care. Aim 3: Develop and refine high-impact strategies to improve PSA screening cascades. Methodology: Aim 1 will explore facility-level variation of key steps in contemporary VHA screening cascades, assessing drivers of this variation and focusing on patterns indicating potential overscreening of low-benefit Veterans, underscreening of higher-benefit Veterans, and inefficiencies in biopsy and treatment practices. This will identify potential opportunities for improvement and direct Aim 3 intervention assessments. Aim 2 will adapt an established, NCI-funded microsimulation model to reflect VHA-specific prostate cancer care, incorporating facility-level differences and unique Veteran risk factors and enabling simulation of improvement strategies. Aim 3 will use the VHA-specific microsimulation model to test and refine strategies, such as adjusting screening intensity by age and risk level or using pre-biopsy MRI. To ensure they are impactful and feasible, the most promising strategies will then be refined through a modified Delphi expert panel of multidisciplinary stakeholders, Path to Translation/Implementation: The project will yield a set of evidence-based strategies for improving screening efficiency and patient outcomes, tailored to address the specific inefficiencies in current VHA care cascades. These insights will be disseminated through professional channels, including through multiple research publications and presentations, seeding an effort to establish a VHA prostate cancer screening learning community focused on implementation and iterative refinement of model-informed interventions.

U.S. National Science Foundation

The Improving Undergraduate STEM Education:Computing in Undergraduate Education (IUSE: CUE) program aims to better prepare a wider, more diverse range of students to collaboratively use computation across a range of contexts and challenging problems. With this solicitation, the National Science Foundation focuses onre-envisioninghow to teach computing effectivelyto a broad group of students,in a scalable manner, with an emphasis on broadening participation of groups who are underrepresented andunderservedby traditional computing courses and careers.

U.S. National Science Foundation

Synopsis of Program: The fields of science, technology, engineering, and mathematics (STEM) hold much promise as sectors of the economy where we can expect to see continuous vigorous growth in the coming decades. STEM job creation is expected to outpace non-STEM job creation significantly, according to the Commerce Department, reflecting the importance of STEM knowledge to the US economy. The National Science Foundation (NSF) plays a leadership role in developing and implementing efforts to enhance and improve STEM education in the United States. Through the NSF Improving Undergraduate STEM Education (IUSE) initiative, the agency continues to make a substantial commitment to the highest caliber undergraduate STEM education through a Foundation-wide framework of investments. The IUSE: EDU is a core NSF STEM education program that seeks to promote novel, creative, and transformative approaches to generating and using new knowledge about STEM teaching and learning to improve STEM education for undergraduate students. The program is open to application from all institutions of higher education and associated organizations. NSF places high value on educating students to be leaders and innovators in emerging and rapidly changing STEM fields as well as educating a scientifically literate public. In pursuit of this goal, IUSE: EDU supports projects that seek to bring recent advances in STEM knowledge into undergraduate education, that adapt, improve, and incorporate evidence-based practices into STEM teaching and learning, and that lay the groundwork for institutional improvement in STEM education. In addition to innovative work at the frontier of STEM education, this program also encourages replication of research studies at different types of institutions and with different student bodies to produce deeper knowledge about the effectiveness and transferability of findings. IUSE: EDU also seeks to support projects that have high potential for broader societal impacts, including improved diversity of students and instructors participating in STEM education, professional development for instructors to ensure adoption of new and effective pedagogical techniques that meet the changing needs of students, and projects that promote institutional partnerships for collaborative research and development. IUSE: EDU especially welcomes proposals that will pair well with the efforts of NSF INCLUDES (https://www.nsf.gov/news/special_reports/nsfincludes/index.jsp) to develop STEM talent from all sectors and groups in our society. For all the above objectives, the National Science Foundation invests primarily in evidence-based and knowledge-generating approaches to understand and improve STEM learning and learning environments, improve the diversity of STEM students and majors, and prepare STEM majors for the workforce. In addition to contributing to STEM education in the host institution(s), proposals should have the promise of adding more broadly to our understanding of effective teaching and learning practices. The IUSE: EDU program features two tracks: (1) Engaged Student Learning and (2) Institutional and Community Transformation.

U.S. National Science Foundation

Synopsis of Program: The fields of science, technology, engineering, and mathematics (STEM) hold much promise as sectors of the economy where we can expect to see continuous vigorous growth in the coming decades. STEM job creation is expected to outpace non-STEM job creation significantly, according to the Commerce Department, reflecting the importance of STEM knowledge to the US economy. The National Science Foundation (NSF) plays a leadership role in developing and implementing efforts to enhance and improve STEM education in the United States. Through the NSF Improving Undergraduate STEM Education (IUSE) initiative, the agency continues to make a substantial commitment to the highest caliber undergraduate STEM education through a Foundation-wide framework of investments. The IUSE: EDU is a core NSF STEM education program that seeks to promote novel, creative, and transformative approaches to generating and using new knowledge about STEM teaching and learning to improve STEM education for undergraduate students. The program is open to application from all institutions of higher education and associated organizations. NSF places high value on educating students to be leaders and innovators in emerging and rapidly changing STEM fields as well as educating a scientifically literate public. In pursuit of this goal, IUSE: EDU supports projects that seek to bring recent advances in STEM knowledge into undergraduate education, that adapt, improve, and incorporate evidence-based practices into STEM teaching and learning, and that lay the groundwork for institutional improvement in STEM education. In addition to innovative work at the frontier of STEM education, this program also encourages replication of research studies at different types of institutions and with different student bodies to produce deeper knowledge about the effectiveness and transferability of findings. IUSE: EDU also seeks to support projects that have high potential for broader societal impacts, including improved diversity of students and instructors participating in STEM education, professional development for instructors to ensure adoption of new and effective pedagogical techniques that meet the changing needs of students, and projects that promote institutional partnerships for collaborative research and development. IUSE: EDU especially welcomes proposals that will pair well with the efforts of NSF INCLUDES (<a href="https://www.nsf.gov/news/special_reports/nsfincludes/index.jsp" target="_blank">https://www.nsf.gov/news/special_reports/nsfincludes/index.jsp</a>) to develop STEM talent from all sectors and groups in our society. For all the above objectives, the National Science Foundation invests primarily in evidence-based and knowledge-generating approaches to understand and improve STEM learning and learning environments, improve the diversity of STEM students and majors, and prepare STEM majors for the workforce. In addition to contributing to STEM education in the host institution(s), proposals should have the promise of adding more broadly to our understanding of effective teaching and learning practices. The IUSE: EDU program features two tracks: (1) Engaged Student Learning and (2) Institutional and Community Transformation.

U.S. National Science Foundation

Improving Undergraduate STEM Education: Directorate for STEM Education