Grants

NIGMS - National Institute of General Medical Sciences

Our research focuses on nicotinic acetylcholine receptors (nAChRs), a diverse family of ligand-gated ion channels known for their role in modulating the release of central nervous system neurotransmitters and their involvement in brain disorders including addiction. Recent studies have highlighted their pivotal roles beyond the central nervous system, influencing significant disease processes such as peripheral neuropathic pain, inflammation, tumorigenesis, and stress-induced pathologies. Over the next five years, our goals include: • Developing a unique library of probes targeted to nAChR subtypes that lack selective ligands. We will accomplish this through structure-activity-relationship studies and mining the plethora of nAChR- targeted peptides refined over millions of years of evolution by carnivorous cone snails. • Exploiting existing ligands as tools to elucidate the structural, functional, and regulatory mechanisms of nAChRs. • Determining the functional role of nAChR subtypes in the pathophysiology of neuropathic pain states. Understanding this mechanism may offer ways to prevent pain development rather than merely masking symptoms and provide an alternative to opioid-based therapies. Our program addresses a critical need by providing potent, precision ligands that selectively target individual nAChRs. By creating highly selective probes and making them widely available to the research community, we will enable researchers to answer fundamental questions. These ligands will not only advance scientific understanding but also drive the development of new therapeutics, potentially serving as lead compounds for innovative treatments. Since specific subtypes of nicotinic receptors are utilized in a broad array of organs and tissues, the wider impact of our work may be felt across multiple fields, accelerating progress in both basic and applied research.

NIA - National Institute on Aging

SUMMARY Alzheimer’s disease (AD) is the most common form of dementia and the fifth leading cause of death among older adults in the United States. Unfortunately, available Food and Drug Administration (FDA)-approved therapeutics for treating AD only offer limited efficacy, largely due to our incomplete understanding of the underlying mechanisms that cause and drive the disease. Genome-wide association studies and immunohistochemistry both implicate neuroinflammation and immune dysfunction as key drivers of AD pathogenesis, but the availability of specific biomarkers to investigate and track the spatiotemporal dynamics and functional phenotypes of immune cells in AD remains extremely limited. Positron emission tomography (PET) is a highly sensitive molecular imaging modality well-suited for the longitudinal study of such biomarkers, with demonstrated utility for non-invasive, in vivo interrogation of biochemical processes. Existing PET biomarkers of neuroinflammation (e.g., the translocator protein 18kDa; TSPO) suffer from significant drawbacks, including non-specific expression across multiple cell types in the central nervous system (CNS) and an inability to distinguish between beneficial and harmful inflammatory processes. To address this unmet need, we identified G protein-coupled receptor 84 (GPR84) as a promising biomarker of pro-inflammatory innate immune responses in the context of AD. Specifically, my preliminary data showed that GPR84 expression is significantly upregulated in human myeloid cells following pro-inflammatory stimulation and in rodents after lipopolysaccharide challenge; upregulation is also observed in the brains of the 5xFAD AD mouse model. Excitingly, we developed two lead GPR84-specific PET radiotracers, [11C]GLPG-38 and [18F]MGX-110S, that cross the blood-brain barrier (BBB) in healthy rodents and enable sensitive detection of harmful inflammatory immune responses in vivo. In this proposal, I aim to evaluate the sensitivity and specificity of our two novel GPR84-PET radiotracers for quantifying pro-inflammatory immune responses in human cells and a mouse model of systemic and neuroinflammation (Aim 1). I will also assess radiotracer performance in the 5xFAD mouse model of AD and analyze the spatial overlap between radiotracer binding and immune cell markers in human AD postmortem brain tissues from multiple disease stages compared to healthy controls, employing in vitro autoradiography and advanced spatial biology techniques to further establish translational potential of each radiotracer (Aim 2). Successful completion of these aims will result in characterization of two novel GPR84-PET radiotracers, assessing their suitability for in vivo imaging of neuroinflammation and the specific innate immune cell populations they target. Ultimately, translation of these innovative PET radiotracers into clinical practice will significantly enhance our understanding of AD pathogenesis, facilitate targeted therapeutic development, and enable precise monitoring of treatment efficacy, ultimately paving the way for improved outcomes for patients with AD.

NSF

With the support of the Chemical Synthesis Program of the Division of Chemistry, Professor Alison Frontier of the Department of Chemistry at the University of Rochester is studying anomalous forms of known cyclization reactions. Some of the reactions chosen for exploration in this project lie at the interface between two well-defined reaction classes that are understood by the community to operate according to different sets of rules. These rules are not well understood. A central goal of the program is to learn more about these ambiguous, underexplored reactions, and understand the behavior of systems designed to occur at the “edges” of an accepted paradigm of reactivity. Other anomalous reactions slated for investigation are expected to enable the Frontier lab to build three-dimensional molecules with unique spatial arrays of carbon, nitrogen and oxygen atoms. These structural features are critical to the behavior of small molecules, and new arrays could uncover new possibilities for chemical reactivity or biological activity. The research conducted by Professor Frontier and her students will expand the range of three-dimensional molecules that can be assembled using chemical methods. Professor Frontier also continues to develop and maintain the “Not Voodoo” website, an educational resource she created in 2004. The site is designed to help students demystify laboratory protocols and procedures. It serves hundreds of organic experimental chemists each day, from students just beginning independent research, to advanced students looking for tips or tricks. In this program, all three research projects focus on anomalous versions of otherwise well understood reactions. The first two projects will explore reactions at the edges of known electrocyclic chemistry. In project 1, the team will explore the interface between electrocyclic and ionic reactivity, seeking to characterize a large group of pentannulation reactions of ambiguous classification. The examples have been collected over many years, comprising cases from the PI’s work and others that stand out as atypical and potentially misclassified. In project 2, the team aims to extend the boundaries of electrocyclic reactivity by developing synthetically useful higher-order cationic electrocyclizations and evaluating both periselectivity and degree of pericyclicity. The findings from projects 1 and 2 will establish parameters for classifying cyclization reactions, which can be applied by members of the community to characterize a new or existing reaction. In project 3, Professor Frontier and coworkers will develop nonlinear polyene cyclizations for the synthesis of highly functionalized, topologically complex heterocycles. When the p-orbital systems of polyene reactants are arranged in a nonlinear fashion, and cationic chemistry is initiated, a combination of cyclization and [1,2]-rearrangement processes can ensue. Through experimentation and analysis, the lab will learn to control these nonlinear cascades. Professor Frontier will also execute expansions and improvements within the Not Voodoo website she created in 2004. Activities will include routine maintenance, compiling case studies that highlight problem-solving strategies used by experts, updating and reorganizing existing content, and adding new technical content. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary This research project seeks to develop and characterize a novel mouse model to address the limitations of current systems for studying mucosal-associated invariant T (MAIT) cells. MAIT cells are a conserved subset of T lymphocytes that bridge innate and adaptive immunity by recognizing microbial metabolites presented by MR1 molecules. They play critical roles in infection control, cancer immunity, and tissue homeostasis. Despite their functional importance, MAIT cells are rare in commonly used laboratory mouse strains, including C57BL/6 (B6), which restricts their study under physiological conditions. Existing approaches, such as TCR transgenic mice or artificial expansion through infection, alter the natural TCR repertoire or rely on inflammation, complicating the study of MAIT cells' development and function. This proposal leverages a genetic engineering strategy to generate the MAIT-Boost Knock-In (MBKI) mouse model, which increases MAIT cell frequency while maintaining natural TCR diversity and thymic selection. By replacing Trav19 with Trav1 and Traj56 with Traj33, the MBKI model redirects TCRa recombination to favor the canonical Trav1-Traj33 configuration required for MAIT cell development. This approach is designed to boost MAIT cell numbers without the unintended consequences of existing models, offering a physiologically relevant system for studying their biology. The project aims to characterize the frequency, tissue distribution, and functional properties of MAIT cells in MBKI mice. It will also assess the broader impact of these modifications on TCRa rearrangement dynamics and other immune subsets, including gd T cells and iNKT cells. Finally, the MBKI model will be used to evaluate whether increased MAIT cell frequency enhances melanoma tumor control, addressing their potential for cancer immunotherapy. This work will provide fundamental insights into MAIT cell biology and create a platform for developing therapeutic strategies targeting infections, cancer, and immune dysregulation.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Sialoglycans or Sias, which are abundant on cell surfaces and in secreted molecules, play key roles in various biological processes, interact with both commensals and pathogens, and change over time in response to environmental signals. However, most of this complexity and variation remains poorly characterized by traditional techniques, using plant lectins, sialidases or antibodies, whose preferences are limited and/or uncertain. Meanwhile mass spectrometry methods can overlook crucial aspects of Sia diversity and/or fail to elucidate native Sia structures in biological systems. To address these challenges, the U01CA199792 grant supported by the NIH Common Fund Glycoscience Program took advantage of naturally evolved microbial molecules (bacterial adhesins, toxin subunits and viral hemagglutinin-esterases) that can recognize sialoglycans with defined specificity. Multiple classes of Sialoglycan Recognizing Probes (SGRPs) with specificity defined by sialoglycan microarray studies were engineered as tagged probes, each with a corresponding non-binding mutant as a negative control. The optimized panel of SGRPs can be used in methods common in most bioscience labs, such as ELISA, western blot, flow cytometry and histochemistry. In Phase I, we propose continued development and validation of six SGRPs (SGRP1, SGRP2, SGRP3, SGRP5, SGRP6, and SGRP8). We will reproduce SGRP1, SGRP2, SGRP3, and SGRP8 based on previously established methods and further validate and optimize their applications in various laboratory techniques across diverse biological sample types. SNA, a plant-derived lectin, was selected as SGRP6 due to its unmatched specificity for α2-6 sialoglycans. Since no other microbial molecules surpass its specificity, we will develop a recombinant SNA protein with an AviTag to overcome the limitations of the plant-derived form, ensuring consistent and reproducible production. We will also develop a non-binding mutant control for the recombinant SNA. SGRP5 is an affinity-purified chicken IgY polyclonal antibody against Neu5Gc sialoglycans, which is limited for long-term use due to finite supply and risk of future non-reproducibility. We propose to develop chicken IgY monoclonal antibodies targeting all common forms of Neu5Gc sialoglycans, providing a more durable and reproducible solution for routine use. In Phase II, we will further develop and optimize SGRPs (SGRP4, SGRP7, and SGRP9) that specifically recognize 4, 7, and 9-O-acetylated sialoglycans, which are common modifications present in many mammalian cells. SGRP probes could revolutionize the analysis of sialoglycans by making it simpler, more efficient, affordable and accessible, allowing nonexperts using common laboratory techniques to find interesting sialome patterns in biological systems. They also provide tools for real-time monitoring of glycosylation patterns in biopharmaceutical production, ensuring consistency and quality. Our goal is to ensure these probes become readily available to the research community, driving progress across multiple biomedical disciplines.

NIGMS - National Institute of General Medical Sciences

Abstract/Summary: The Fernández Lab seeks to understand how environmental cues and internal physiological states are processed by the nervous system to drive behavior. Our current research focuses on the circadian clock, which allows organisms to maintain internal temporal order and anticipate daily changes in their environment. While the molecular mechanisms underlying the circadian clock are well characterized, the processes by which clock neurons develop and establish connections with each other and with downstream pathways remain poorly understood. Drosophila is an excellent model due to the conservation of the molecular circadian clock and the presence of network motifs resembling those in mammals. Emerging evidence from both mammalian and invertebrate models suggest that core circadian clock genes, some of which are expressed prior to the initiation of the molecular clock, play critical in neuronal development and physiology beyond their established functions in molecular timekeeping mechanism. We recently showed that this is the case for the Drosophila clock gene cycle. When downregulated exclusively during development, cycle leads to altered clock neuron morphology and the loss of adult behavioral rhythms. Our ongoing and future research is aimed at understanding how clock neurons establish their connectivity patterns during development to form a synchronized network of neurons that drives rhythmicity, from gene expression to complex behaviors. Specifically, we will examine the developmental roles of the clock genes cycle and Clock in shaping the connectivity of the main circadian pacemaker neurons and other early-born clock neurons. Notably, these genes are expressed in clock neurons before molecular oscillations can be detected, and we will assess how their downregulation impacts gene expression pathways that influence early-developmental neuronal morphology and connectivity. Additionally, we will examine how various groups of clock neurons respond to key synchronizing signals throughout development, as well as to stimulation of other clock neuron classes. Our recent findings indicate that female circadian rhythms are more resilient to loss of synchronizing factors and suggest that the relative hierarchy of circadian oscillators is sexually dimorphic. We aim to determine the extent to which sexual dimorphism in circadian timekeeping emerges during development and the contributions of sex determination genes in establishing sex differences. Our research program aims to understand how clock neurons develop, communicate, and form precise connections to generate a functional network that drives timekeeping. Our results will contribute to a broader understanding of the mechanisms underlying neuronal development and behavioral plasticity.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Excessive fructose consumption from beverage consumption and processed food is a major driver of obesity and metabolic syndrome, largely due to increased uric acid (UA) levels from fructose metabolism in the liver. Elevated UA, majority of which is in the more soluble anionic form called urate, is directly linked to metabolic issues including leptin resistance (influencing satiety/hunter) and fat accumulation leading to non- alcoholic fatty liver disease. The link between UA and fructose-induced obesity highlights the potential of urate-lowering therapies (ULT) to mitigate fructose-induced obesity. Pegloticase is a PEGylated uricase enzyme clinically approved to treat tophaceous gout patients who do not respond to other ULT; it is the only treatment available for repeated dosing that can reduce serum UA by directly breaking down UA. Other ULT target pathways that either reduces UA synthesis, or induces greater renal clearance; thus, pegloticase’s ability to directly breakdown UA may offer superior efficacy in reversing fructose-induced obesity. However, pegloticase has not been tested to reverse fructose-induced obesity or metabolic syndrome, in part due to its safety profile. Pegloticase in its current form induces anti-PEG antibodies (APA) in nearly 90% of the subjects, leading to loss of efficacy in nearly 60% of the patients, and high incidence of allergic reactions culminating in a black box warning for anaphylaxis on its product label. While such safety profile may be acceptable for a highly debilitating and painful acute inflammatory conditions with no other treatments, it is unsuitable for use in obesity applications. To overcome the clinical shortcoming of pegloticase, Mucommune has licensed a technology that effectively overcomes pre-existing APA and mitigate APA induction, without requiring broad immunosuppression. The approach uses high molecular weight free PEG to saturate circulating APA and B-cell receptors on APA+ B-cells, thereby reducing the “hapten” effect of PEG-drugs. Our prior work shows that free PEG suppresses APA induction against pegloticase in animal models, restores drug circulation in the presence of high APA titers, and does not further induce APA. In highly sensitive swine models, free PEG completely eliminates hypersensitivity reactions to PEGylated drugs, greatly enhancing the safety and efficacy of PEGylated treatments. This proposal seeks to evaluate whether free PEG reformulated pegloticase (MM010) can be repeatedly dosed into animals to sustain ULT that safely and effectively block fructose-induced obesity. In Aim 1, we will produce and characterize pegloticase, which will be used in animal studies of fructose-induced obesity in Aim 2. We will file a pre-IND package (Aim 3) with the FDA to gain guidance on the anticipated preclinical and clinical development path. Successful completion of this project will position MM010 as a novel option in treating hyperuricemia and metabolic disorders, potentially benefiting millions with inadequate UA management.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract This K23 award will enable Dr. Shastry (principal investigator, PI) to become an independent physician- scientist focused on improving emergency department (ED) care for patients with opioid use disorder (OUD) through the development and evaluation of behavioral and clinical interventions. Opioid overdose deaths continue to exert a significant mortality burden, with over 50,000 deaths in the United States in 2024. Buprenorphine (BUP), a medication for opioid use disorder (OUD), has been shown to decrease opioid overdose mortality and morbidity and can be initiated in the ED. However, BUP adherence and treatment retention is challenging, with high rates of patient attrition, particularly in the first month after ED BUP initiation. The first month after ED BUP initiation is also a uniquely high-risk time with regard to recurrent overdose and mortality. Therefore, there is an essential need to understand barriers to BUP adherence in the first month after ED BUP initiation, and to develop and test behavioral and clinical interventions to address these barriers. During this K23, Dr. Shastry (PI) will: (1) characterize barriers to ED BUP adherence and treatment retention in the first month following ED BUP initiation using mixed-methods; (2) develop and refine a targeted multi- component behavioral and clinical intervention aimed at supporting patients in the first month after ED BUP initiation; and (3) evaluate feasibility, acceptability and preliminary efficacy of this post-ED BUP initiation support intervention through a pilot randomized controlled trial (RCT). To achieve the Specific Aims of her K23 research project, Dr. Shastry (PI) has prepared a research and career development training plan comprised of rigorous mentorship and didactic coursework in mixed-methods research, intervention development and clinical trials. She also has assembled a nationally recognized mentorship team with extensive and renowned content expertise in these areas. Her proposed research and career development plan will enable Dr. Shastry’s (PI) transition to an independent physician-scientist focused on improving ED OUD care through behavioral and clinical interventions. Completion of her K23 research project will provide Dr. Shastry (PI) with crucial preliminary data to estimate the effect size of the novel post-ED BUP initiation support intervention’s efficacy on increasing treatment retention and reducing overdose, informing her subsequent large multi-site R01 RCT evaluating the efficacy of this intervention.

NIH

Significance to VA: This project addresses the need to support older Veterans’ functional recovery during transitions from hospital to home. Functional decline after hospital discharge results from a complex interplay between pre-existing health conditions, physiological stressors, and reduced mobility throughout hospitalization. Veterans are particularly vulnerable to functional decline after discharge due to their high burden of physical and psychological conditions. Transitions from hospital to home serve as important junctures to address functional decline, but Veterans are often discharged without a comprehensive functional evaluation, putting them at increased risk for negative post-hospital outcomes. The Coordinated Transitional Care (CTraC) program is a nurse-led transitional care intervention developed to improve Veterans’ transitions home after hospitalization. CTraC has demonstrated significant benefits for Veterans, including reduced readmissions, improved patient safety, and increased engagement in care. Yet, the existing CTraC protocol misses a critical opportunity to include assessment, intervention, and care coordination supportive of Veterans’ functional recovery. Innovation and Impact: This project aims to develop and test a novel, function-focused protocol for VA’s CTraC program. The goal of this work is to improve functional outcomes for Veterans, empowering them to achieve greater independence and quality of life. This work is responsive to VA’s strategic goals and the mission of VA RR&D which seeks strategies to mitigate the impact of chronic conditions for aging Veterans. This work is also well-aligned with VA priorities such as integrating Whole Health care practices and becoming the largest integrated Age-friendly Health System via delivery of care aligned with the 4Ms: mobility, mentation, medication, what matters. Specific Aims: Aim 1: Develop and refine CTraC-FIT (Functional Independence aT home) for Veterans at risk of functional decline transitioning from hospital to home. Aim 2: Examine the feasibility and acceptability of CTraC-FIT in a pilot randomized controlled trial. Methodology: This project uses a mixed-methods approach with two phases. Phase 1 focuses on intervention development and refinement. Qualitative interviews with VA clinicians (n=15) will inform development of the CTraC-FIT protocol. A small-scale nonrandomized pilot (n=5 Veterans) will assess initial intervention feasibility and acceptability. Qualitative feedback from Veterans will guide refinement of the intervention protocol and study procedures. Phase 2 focuses on pilot testing. A pilot randomized controlled trial will compare CTraC-FIT to enhanced usual care in 40 older Veterans at risk of functional decline (1:1 comparison; n=20 per group). Feasibility and acceptability of the intervention protocol will be measured via surveys and qualitative interviews with Veterans, and surveys with clinicians (n~20). Exploratory outcomes of quality of life and physical, cognitive, and social function will be measured via self-reported and performance-based quantitative assessments at baseline, post-intervention, and 3-months post-intervention. Path to Translation/Implementation: The results of this CDA-2 will lay the groundwork for a future RR&D Merit application to support a multi-site Stage II randomized controlled trial of the CTraC-FIT intervention. By leveraging the existing successful CTraC program and infrastructure, the CTraC-FIT intervention has strong potential for widespread implementation across the VA healthcare system. This work is aligned with key VA priorities, poised to enhance transitional care delivery, and designed to support Veterans’ functional recovery after hospital discharge to home.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY: This is a submission for a National Institutes of Health R21/R33 award aiming to develop and validate an innovative, inexpensive multi-modal digital stethoscope capable of simultaneous automated lung sound and respiratory rate analysis, and mobile phone interoperability with an electronic health (eHealth) DHIS2 platform for real-time LRI and antibiotic surveillance in LMICs (R21 period), and then evaluation of the multi-modal digital stethoscope and eHealth system using an individually randomized controlled trial (R33 period). The lower respiratory infection (LRI) pneumonia is the leading infectious cause of death among children globally and in sub-Saharan Africa, but appropriate, accurate and user-friendly LRI diagnostics suitable for low-income and middle-income countries (LMICs) are severely lacking. This results in misdiagnosis and death, as well as inappropriate antibiotic use that contribute to overall rising antibiotic resistance rates globally. We aim to develop, validate, and rigorously evaluate the implementation of an innovative, inexpensive multi- modal digital stethoscope capable of simultaneous automated lung sound and respiratory rate analysis, and mobile phone interoperability with an electronic health (eHealth) DHIS2 platform for real-time LRI and antibiotic surveillance in LMICs. We hypothesize that a multi-modal digital stethoscope will meet pre-specified performance benchmarks and its implementation within an eHealth platform will address key LRI diagnosis implementation outcomes. To accomplish our overall project goal we will build upon nearly a decade of our multi-disciplinary digital stethoscope research and development across seven LMICs, our previous successful LMIC pulse oximeter device development using a human centered design (HCD) strategy, and evidence from our recent randomized controlled trial of antibiotic treatment in Malawi that suggested the vast majority of non-severe LRIs did not require antibiotics at all. During the two-year R21 period we will apply the human centered design approach to develop a multi-modal digital stethoscope and eHealth system (Aim 1). The device will be validated in a sound laboratory and field tested in various clinical settings with a range of practitioners in Cape Town, South Africa. We will then implement the multimodal digital stethoscope and DHIS2 system at a variety of facilities (Khayelitsha Hospital, and two primary care clinics) that serve a large township in Cape Town, South Africa and conduct an individual randomized controlled trial to evaluate `correct LRI diagnosis' as the primary outcome (Aim 2), as well as secondary implementation outcomes. Successful completion of the research described in this application could lead to broader scale-up of an affordable, sustainable interoperable LRI and antibiotic use eHealth system with advanced diagnostic technology contextually appropriate for LMICs, where most pediatric deaths from LRIs occur.

Oregon State University Libraries

OSU will create a web-based tool, optimized for use in a mobile environment that takes the University of Oregon’s Building Oregon: Architecture of Oregon and the Pacific Northwest collection, and makes it accessible to users in a mobile app, leveraging the tools and capabilities that the mobile environment provide.  Building Oregon is a traditional digital collection of approximately 20,000 images representing approximately 5,000 cultural properties from nearly 500 sites. Once the mobile tool has been created, OSU Libraries will release the framework on open source code repositories, like GitHub, for other libraries with digital collections to use to mount their own digital collections or repurpose existing digital collections in a mobile environment.

Oregon State University Libraries

This project will address the need for in-depth archives and records management training for Oregon's nine federally recognized Indian tribes. Establishing formal and sustainable archives and records management programs by the tribes has been difficult in part due to the lack of affordable and location-accessible training opportunities for tribal members with responsibilities for records. The need for this training will be met through the planning and implementation of a one-week institute that will cover the basic concepts and requirements for tribes to establish or improve their archives and records management programs. The training will be based in Oregon and will be at no or low cost to tribal participants.

Oregon State University Libraries

The second year of this project will address the need for in-depth archives and records management training for Oregon's nine federally recognized tribes. The need for this training will be met through the planning and implementation of a one-week institute that will cover basic and advanced concepts and requirements for tribes to establish or improve their archives and records management programs. The training will be based at Oregon State University and will be at no or low cost to tribal participants.

NIAID - National Institute of Allergy and Infectious Diseases

Chronic rhinosinusitis (CRS), defined by persistent inflammation and/or infection of the nasal cavity and paranasal sinuses, has a prevalence of 3.6% in the United States adult population, equating to approximately 13 million affected individuals.1,2 Symptoms include nasal obstruction, facial pressure, nasal drainage, and hyposmia.3,4 Bacteria implicated in the pathogenesis of CRS can form biofilms, which are communities of bacteria that coordinate behavior through quorum sensing—a cell density-dependent signal transduction process—to proliferate.25 Increasing evidence suggests that biofilms play an important role in the etiology and morbidity of CRS.26-30 Gram-negative organisms, including PA, are potent biofilm formers and are frequently observed in treatment-resistant CRS.31,35,36 Biofilms, in contrast to planktonic bacteria, harbor unique characteristics that imbue them with a 10-1000 fold higher resistance to antimicrobials. In an evaluation of patients with medially recalcitrant CRS, biofilms were associated with: (i) worse CRS symptom score, (ii) worse radiologic appearance, (iii) recurrent infections, (iv) increased need for surgical intervention, and (v) in those undergoing sinus surgery, poorer surgical outcomes versus non-biofilm CRS.41-43 In many cases, treatment using conventional antibiotics would require a 60-1,000-fold increase in dose, which would be clinically unsafe.44 Topical antibiotic treatment, such as mupirocin nasal irrigations, can be more effective in biofilm treatment, but have demonstrated only short-term efficacy.45,46 Consequently, there is a pressing need for more effective antibacterial therapies in CRS. The goal of this proposal will be achieved through two interconnected specific aims. Specific Aim 1: For clinical-translation purposes, zMP-NO.2 will be synthesized and characterized prior to being evaluated for in vitro antibacterial activity against P. aeruginosa and other bacterial strains relevant to CRS as well as for preliminary cytotoxicity. Specific Aim 2: The concentrations of zMP-NO.2 in a gel vehicle required to deliver sufficient NO to the sinus epithelial tissues to achieve bactericidal activity will be established; this formulation will then be used to assess zMP-NO.2 efficacy in treating P. aeruginosa in a rabbit in vivo sinusitis model. At the conclusion of this Phase 1 study, an Optimized Test Formulation will be established with a defined concentration of zMP-NO.2 suitable for further formulation development, scale-up, safety studies, and ex vivo efficacy studies in Phase 2.

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT The majority of persons living with cognitive impairment (PLWCI) are discharged after seeking care in the emergency department (ED), with informal care partners (e.g. family members, friends) subsequently providing a significant amount of hands-on care and navigation of health-related and social needs within this vulnerable time period. There exists a critical need to develop pragmatic ED care transition interventions to support care partners given the growing population of PLWCI seeking emergency care, the adverse outcomes that PLWCI experience after ED discharge, the outcome interconnectedness between PLWCI and care partners, and the limited generalizability and effectiveness of interventions to date. The candidate, Dr. Gettel, is an emergency physician at the Yale School of Medicine with a track record of early success and preliminary findings through an NIA GEMSSTAR Award identifying that care partners of PLWCI experienced poor, if any, communication during ED discharge. Digital health interventions (e.g. text messaging) have previously shown promise as a pragmatic tool for communication in various ED populations, yet no evaluations have assessed these approaches in the population of care partners of PLWCI despite their acceptance of digital health and the capability of digital health tools to disseminate information beyond the physical confines of the ED encounter. The objective of this proposal is to develop and pilot test the CAre Partner Text message intervention to improve futURE outcomes (CAPTURE), an ED care transition intervention delivered via automated tailored text messaging that will provide information, core medical reminders and behavioral strategies, and practical support to care partners of PLWCI. Sequential exploratory mixed-methods approach will be used to achieve the three aims: 1) Elucidate facilitators and barriers to the use of an ED-based text message care transition intervention among care partners of PLWCI; 2) Develop and iteratively refine the CAPTURE using user- centered design methods for care partners of PLWCI quantitatively measuring usability, feasibility, and acceptability; and 3) Determine the feasibility and preliminary efficacy of the CAPTURE implementation after an ED visit in care partners of PLWCI compared to a care partner population receiving usual care. Responsive to the “National Institute on Aging: Strategic Directions for Research, 2020-2025”, findings of this proposal will expand supports and address the special needs of care partners of PLWCI. During the award period, Dr. Gettel will pursue career development training activities leveraging the team’s mentorship expertise in the domains of: geriatric emergency medicine; text message interventions; ADRD and care partners; patient- and caregiver-reported outcome (PCRO) measurement; embedded pragmatic clinical trial (PCT) design; and implementation science. Findings will inform an NIA R01 proposal to assess the real-world efficacy and effectiveness of the CAPTURE implementation and its impact on PCROs as part of a multisite embedded PCT.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Drug use disorders (DUDs), a subclassification of substance use disorders (SUDs) involving the misuse of non-alcohol illicit drugs, remain a major public health crisis in the U.S., affecting 27 million persons and contributing to over 100,000 overdose deaths annually. Among those with DUDs, 30% to 50% have a primary sexual partner who also has a DUD—dual-DUD couples. These couples experience significantly poorer treatment outcomes, including higher relapse rates and lower treatment engagement, compared to individuals without a drug-using partner. Despite the well-documented reciprocal influence of partners on each other’s substance use, current treatment paradigms remain predominantly individual-focused, overlooking the relational context in which substance use and recovery occur. The absence of couples-based treatment models designed specifically for dual-DUD couples represents a critical gap in the addiction treatment landscape. This study aims to address this gap by developing and piloting a novel couples-based intervention tailored to the needs of dual-DUD couples who use opioids and/or stimulants. Grounded in the Recovery Capital framework and the SUD Couple System model, this study will incorporate a Co-Creation approach to intervention development, ensuring meaningful engagement from stakeholders, including affected couples, treatment providers, and administrators. The research design follows an R61/R33 phased structure, integrating the Intervention Mapping + Adapt (IMA) framework for intervention development with the Consolidated Framework for Implementation Research (CFIR) to guide and evaluate implementation strategies. In the R61 phase, formative mixed-methods research will be conducted to identify key determinants and recovery assets influencing drug use behavior and treatment outcomes among dual-DUD couples (Aim 1). These findings will inform the development and adaptation of a couples-based treatment program using an intervention mapping approach (Aim 2). The R33 phase will involve finalizing intervention materials and implementation strategies (Aim 3), conducting a dual-site pilot randomized controlled trial (RCT) at SUD treatment centers in Rochester, NY, and Newark, NJ (Aim 4), and evaluating post-pilot data to refine the intervention and assess readiness for a confirmatory Hybrid Type 2 effectiveness trial (Aim 5). This project aligns with the objectives of RFA DA-26-024 (R61/R33 Exploratory/Developmental Phased Award), which seeks to engage loved ones in the recovery process and enhance access to evidence-based care for those affected by DUDs. develop and test dyadic approaches to support engagement in evidence-based care for individuals in DUD-affected relationships. By addressing a longstanding treatment gap, this study aims to contribute to the broader goal of reducing substance use-related harm and improving public health through innovative, relationship-centered care models.

NIA - National Institute on Aging

PROJECT ABSTRACT This is a National Institute on Aging (NIA) K23 proposal from Adrian Haimovich, MD/PhD, an emergency medicine physician-scientist at Beth Israel Deaconess Medical Center and Harvard Medical School. Dr. Haimovich is committed to becoming a national leader at the intersection of geriatric acute care, data science, and electronic health record (EHR) interventions. While 75% of adults aged ≥65 years will visit an emergency department (ED) within six months of dying, few ED clinicians incorporate patient end-of-life values into medical treatment plans leading to goal-discordant care. In alignment with the new CMS Age Friendly Hospital Measure, the goal of this proposal is to develop an EHR-embedded, transdisciplinary serious illness communication intervention for the emergency department (SIC-ED) to help emergency clinicians solicit the goals, values, and preferences of older adults at the end-of-life and incorporate them into decision-making. With funding from an NIA T32 at Hebrew SeniorLife and a Harvard KL2, Dr. Haimovich developed the Geriatric End-of-life Screening Tool (GEST), an automatable logistic regression algorithm that uses EHR data to identify older adults in the ED with limited life expectancy for the SIC-ED intervention. Dr. Haimovich also performed a survey of 100 ED patients aged ≥65 years, finding that only 37% of older adults in the ED had spoken to their doctor about the type of care they would want to receive if they were very sick or at the end of life. To address this gap, SIC-ED will incorporate four evidence-based facilitators of serious illness communication: (1) proactive patient identification with GEST, a multilevel intervention comprised of (2) a patient activation questionnaire and (3) engages transdisciplinary ED teams (e.g., physicians, nurses, and social workers), and (4) be designed for EHR integration. Following the SALIENT EHR implementation framework, Dr. Haimovich will (1) prospectively validate GEST over 3 months, (2) develop SIC-ED using a stakeholder-informed human- centered design process, and (3) assess feasibility, acceptability, and preliminary efficacy in a two-site single- arm pilot. The proposed 5-year plan accelerates Dr. Haimovich's career development as an independent physician-scientist through training in (1) implementation of EHR predictive models, (2) human centered design of EHR interventions, (3) conduct of clinical trials, and (4) leadership in geriatric emergency care. Dr. Haimovich's mentorship team incorporates research expertise in implementing shared decision-making with older adults, ED clinical trials, and ED palliative care. The culmination of this career development award will ensure Dr. Haimovich has the advanced research skills and knowledge required to conduct a large, multi-site trial of SIC-ED. The goal of this research is to establish SIC-ED as the national standard of care to help ED clinicians incorporate the goals, values, and preferences of seriously ill older adults in their care.

NCI - National Cancer Institute

Moderate-to-severe cancer pain is common in patients with advanced cancer and is often effectively treated with prescription opioids. Effective pain management is crucial for optimal quality of life and health outcomes in these patients. However, the emergence of the opioid crisis in the United States has sparked widespread fears about the use of opioid pain medications, given the potential for negative outcomes such as addiction and overdose. Despite being exempted from restrictive opioid policies, patients with cancer experience adverse consequences of efforts to address the opioid crisis, including stigma associated with prescription opioid use (“opioid stigma”). Based on our recently published Opioid Stigma Framework, we anticipate that opioid stigma results in several proximal (e.g., impaired patient-provider communication, suboptimal health behaviors, emotional distress, maladaptive coping skills) and long-term health consequences (e.g., less effective pain management, reduced health-related quality of life). Emerging evidence indicates that opioid stigma is common, pervasive, and has the potential to seriously impact patient well-being. However, there are no known interventions to mitigate opioid stigma in patients with advanced cancer. Thus, the proposed project will develop and test a novel behavioral intervention for opioid stigma in an effort to fill this unmet need. Together with her mentors, Principal Investigator Dr. Bulls will explore opioid stigma experiences and treatment priorities reported by 75 patients with advanced, painful cancer using rigorous concept mapping methodology (Aim 1). Next, Dr. Bulls will design a theory-based intervention to reduce negative proximal impacts of opioid stigma in patients with advanced cancer, soliciting feedback from patients and community-engaged institutional resources prior to piloting (Aim 2). Finally, Dr. Bulls will conduct a pilot trial of the intervention with 45 patients with advanced cancer pain to evaluate feasibility and acceptability in preparation for a full-scale randomized controlled trial (Aim 3). This project will facilitate training crucial to Dr. Bulls’ career development: advanced skills in participatory and stakeholder-engaged research methods, in-depth training in behavioral intervention development, and expertise in conducting clinical trials. Dr. Bulls has convened a dedicated, multidisciplinary mentorship team with expertise in essential content and methodological areas including palliative oncology, opioid pain management, health-related stigma, concept mapping, behavioral intervention development and testing, and recruitment of patients living with advanced cancer, among others. This proposal represents a comprehensive training, mentoring, and research plan to support Dr. Bulls’ transition into a successful independent investigator. At the end of the award period, Dr. Bulls will contribute substantially to the field as a leader in behavioral approaches to improve opioid stigma in patients with advanced cancer.

NEI - National Eye Institute

Project Summary/Abstract Vision loss is a devastating medical problem as it can lead to reduced productivity, lower quality of life, and loss of independence. Glaucoma affects over four million Americans and 76.0 million people worldwide, making it the second leading cause of irreversible blindness globally. The disease is characterized by retinal ganglion cell degeneration with consequent loss of the axons that connect the eye to the brain and progressive damage to the optic nerve. Pharmacological and surgical interventions that lower intraocular pressure can slow or even stop retinal ganglion cell degeneration. However, many patients do not seek medical attention until the disease is advanced and others continue to experience disease progression despite treatment, ultimately resulting in the widespread loss of retinal ganglion cells and profound vision loss. Unfortunately, the human retina has minimal regenerative capacity and cannot replace lost retinal ganglion cells, making vision loss in these patients permanent. The candidate’s long-term career goals are to advance our understanding of gene regulatory networks directing retinal ganglion cell differentiation during development and to apply these insights to formulate strategies for regenerating retinal ganglion cells from dormant progenitor cells in the adult retina. The proposed career development and training plans will allow the candidate to acquire further expertise in retinal development and regeneration. By learning additional cutting-edge experimental techniques, the candidate will also enhance the scientific rigor and impact of their research program. In the first specific aim, the candidate will investigate the role of transcription factor Pou2f2 in retinal ganglion cell development using conditional gene deletion, as well as gain-of-function by in vivo electroporation of postnatal progenitors. In the second and third specific aims, the candidate will perform an in vivo screen of more than 40 candidate transcription factors to identify a combination capable of reprogramming Müller glia into retinal ganglion cells. Further studies will focus on characterizing induced retinal ganglion cell morphology, laminar position, axon extension, electrophysiology and gene expression. Adaptive optics will be used to longitudinally image the reprogramming process in vivo. Lastly, the candidate will investigate survival and circuit integration of these newly generated retinal ganglion cells in mouse models of glaucoma. Because retinal ganglion cells are widely used as a model for axonal regeneration in vertebrates, these studies have broader implications for regeneration of central nervous system neurons and pathways. The candidate will conduct the proposed research in collaboration with co-mentors Dr. Yvonne Ou and Dr. Xin Duan, and the other members of the advisory committee. Experiments will take place in Rock Hall, where the candidate has dedicated laboratory space in close proximity to all collaborators. The UCSF Department of Ophthalmology is a leading center for vision science research, providing the candidate with access to NEI P30 funded core facilities and extensive university-wide resources. The candidate will also benefit from interactions with the broader neuroscience and stem cell research communities at UCSF.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary The huge breadth and depth of data and knowledge defined by the genome sequence of an organism, and by large numbers of other experimental findings for the organism, requires a database (DB) as a central repository for information about the genome, the biochemical network, and the regulatory processes of that organism. The Pathway Tools software is a robust and comprehensive system for constructing such organism-specific DBs. Path- way Tools enables communities of scientists to create, query, visualize, and analyze organism DBs, and to publish such DBs on the web. The software supports construction of organism DBs that combine a large number of bioin- formatics datatypes, including genome maps, genes, operons, RNAs, proteins, chemical compounds, biochemical reactions, metabolic pathways, and regulatory interactions. Pathway Tools further enables inference of qualitative metabolic reconstructions from sequenced genomes, and the creation of quantitative metabolic flux models from those reconstructions. Such metabolic models enable computational predictions of which genes and reactions within the metabolic network are essential, thus facilitating the design of drugs against disease-causing bacteria. We propose to research and develop several new capabilities to enhance Pathway Tools, including the con- struction of a next-generation metabolic pathway prediction algorithm with improved accuracy based on ad- vanced machine-learning methods. We will also develop tools to support analysis of isotopic labeling experi- ments for metabolomics, to enable researchers to quickly track labeled atoms through biochemical networks. We will integrate multiple software tools for inferring virulence gene annotations, and for searching and comparing virulence genes and pathways. We will also develop tools for reporting the update operations made by a team of curators to aid in managing curation efforts and identifying which automated inference tools are most frequently corrected by curators. Pathway Tools is a mature and production-grade software environment which has been licensed 15,567 re- search groups from around the world, and which has been cited 2,603 times. We propose to maintain the software, such as by installing new versions of its many components, and by supporting the user community through train- ing, documentation, and bug fixing.

National Park Service

Views of nocturnal landscapes free from artificial light are important parts of visitor experience. Artificial light is known to affect the movements and behavior of flying insects, but this phenomenon has not been studied in remote locations that have historically been completely free from artificial light. Energy development in the Great Plains and Intermountain West is introducing bright lights into some of these remote areas. Many ongoing or planned developments are close enough to National Park units that they could affect the nocturnal flying insect fauna in the park, and all of the other species that are linked to those insects.

NIMH - National Institute of Mental Health

PROJECT SUMMARY This proposal will develop a multi-functional interface to measure and modulate the activity of neural organoid cultures. The first generation of this Compliant Reversible Actuator and Detector Leveraging Electrophysiology (Organoid-CRADLE) will include a multi-electrode array (MEA) and light-emitting diodes (LEDs) for optogenetic experiments. The LEDs will interface with NeuroLux’s existing suite of hardware and software for optogenetic experiments, while the MEA will interface with hardware from other established vendors. The Organoid-CRADLE will have several transformational advantages over status quo technologies. The Organoid-CRADLE will use a revolutionary soft robotic structure to grip non-adherent organoid cultures and position electrodes and µLEDs on the organoid surface. Conventional MEAs are flat, making them incompatible with the curved shape of an organoid. Even next-generation 3D MEAs that are curved for compatibility with organoids currently have a static shape. Therefore, it is difficult to design them to perform well with multiple organoids because organoids vary significantly in size and shape, even within a single batch. Our device solves this problem because it has soft arms that gradually curl up from a flat position when pressurized. Instead of being designed to match the shape of a target organoid, the device is designed to conform to the size and shape of whatever organoid it encounters, making it much more versatile than other state-of-the-art devices. Another problem with competing devices is that the contact is not reversible. The Organoid-CRADLE can disengage from the organoid at any time without damaging the device or injuring the organoid. As a result, a single device can record from several different organoids in rotation. Also, an organoid that is used for recording can be released unharmed for use in other procedures. Neither of these approaches is possible with competing devices and both will be highly valued by our target customers. We will prepare this revolutionary product for market by focusing on its geometry, MEA functionality, and optical stimulation functionality. We will optimize the geometry to maximize contact area without inducing injury. We will demonstrate that an array of electrodes can be embedded in the device and validate their ability to record the activity of the organoid. Finally, we will demonstrate that tiny µLEDs can be attached to the device and used to induce activity in appropriately-prepared, light sensitive organoids. The capacity to capture an organoid without injuring it and then release it is useful independent of the other functionality of the device. Similarly, MEA and optical stimulation functionality are also independently valuable. In combination, these features will move organoid electrophysiology from being a challenging assay available only to large, well- resourced labs to being a routine assay available to startups and small academic labs across the world. Therefore, we anticipate that this product will not only quickly dominate the market for organoid electrophysiology but also ultimately expand it by making it more accessible.

NHLBI - National Heart Lung and Blood Institute

Development and Validation of a High-Fidelity Cardiac Presurgical Planning Platform for Congenital Heart Defects Using 3D Printing Technology Background: Congenital heart defects (CHD) affect 1% of infants annually, with greater risk to children born into low socioeconomic status. Many CHD are associated with high infant mortality rates such as hypoplastic left heart syndrome (HLHS), a CHD which is fatal unless treated with complex surgical interventions. By creating Pre-Sure-CHD, a patient-specific preoperative surgical rehearsal and planning platform, Lazarus 3D will facilitate rehearsal of these complex cases, improving survival rates for infants born with CHD - particularly those with low socioeconomic status. Objective: To develop and validate Pre-Sure-CHD, enhancing surgical planning and rehearsal for CHD by providing surgeons with operable, high-fidelity, patient-specific models. Methods: The study comprises three specific aims: Aim 1 involves optimizing synthetic materials to replicate the mechanical properties of cardiac tissues, ensuring realism in the Pre-Sure-CHD models. Aim 2 utilizes proprietary 3D printing technology to create patient-specific prototypes for real CHD cases, informed by CT and MRI imaging data. Aim 3 assesses the content and construct validity of Pre-Sure-CHD through surgical planning refinement, recording changes, and collecting metrics for analysis. Results: The study aims to achieve milestones, including tuning polymers to mimic cardiac tissue properties, completing Pre-Sure-CHD prototypes, and obtaining a Likert scale survey score >3.5 and a 10% improvement in surgical metrics. Conclusion: Successful completion of this project will provide the first cardiothoracic surgical rehearsal platform for CHD, empowering surgeons to optimize their approaches in a risk-free environment. Implications: Pre-Sure-CHD holds the potential to revolutionize surgical planning for critical congenital heart defects, reducing mortality rates associated with these conditions. The project's success will pave the way for a future Phase II clinical study and collaborations with medical institutions, ultimately contributing to improved patient outcomes and healthcare advancement.

NSF

This project aims to serve the national interest by developing an empirically validated tool to assess a student’s knowledge of computing concepts. Such well-designed knowledge assessments, vetted by rigorous design and psychometric processes, are still relatively uncommon in the computer science education community. Moreover, students learn computing concepts in a variety of increasingly different educational contexts: at home, on the job, in a course offered online, or in a traditional classroom. Thus, there is a pressing need for an empirically validated assessment of computing knowledge that works in a variety of educational contexts and with different programming languages. The goal of this project is to design and pilot such a multi-contextual and multi-language assessment by enhancing the existing Second Computer Science 1 (SCS1) course assessment. The new assessment, referred to as SCS1++, will be designed by addressing known issues with the existing SCS1 assessment while also increasing the number of questions on the assessment. Specifically, the project will (1) construct a coherent argument for validity claims of SCS1++ as a whole; and (2) create subscales aligned with the concepts on the assessment to improve the assessment’s formative values. The project will directly inform the research on equitable CS assessment by updating the current SCS1 with improved questions and rigorous validation using advanced psychometric tools. A design-based research approach will be used, based on theory, and the system will be evaluated in real educational settings. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through its Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.