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NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa pose an urgent public health threat. MDR P. aeruginosa is a critical priority global pathogen for which new therapeutic approaches are desperately needed. At UPMC, over 100 patients each year develop serious infections with MDR P. aeruginosa; these infections are difficult to manage, frequently evolve resistance to last-line antibiotics, and are often deadly. There is an urgent need to develop new antimicrobial approaches for the treatment of MDR P. aeruginosa infections. Bacteriophage (phage) therapy is one such approach that has gained significant attention in recent years. We currently treat dozens of patients each year at both UPMC and across the country with phage therapy under compassionate use, which uses personalized phage cocktails to treat resistant bacterial infections in individual patients who have no other viable treatment options. Most of the patients we treat are suffering from MDR P. aeruginosa infections, and in the majority of patients treated thus far, phage therapy improved their clinical status. Despite this success, single patient anecdotes are not sufficient to rigorously test and develop phage therapy for widespread use. Here we propose to systematically assemble and evaluate a multi-phage cocktail targeting diverse MDR P. aeruginosa clinical isolates which can be paired with new β-lactam/β-lactamase inhibitor (BL/BLI) combinations currently used to treat MDR P. aeruginosa infections to improve antibacterial efficacy. Our central hypothesis is that a rationally selected cocktail of P. aeruginosa phages targeting contemporary MDR P. aeruginosa isolates will improve the activity of antibiotics commonly used to treat MDR P. aeruginosa infections. To test this hypothesis, we will leverage a large collection of contemporary MDR P. aeruginosa clinical isolates collected from 28 medical centers across the country as well as a panel of 10 lytic phages that have been previously approved for use in phage therapy to treat patients, and which were safe and well tolerated. In Aim 1, we will assemble a P. aeruginosa-targeting multi-phage cocktail that exhibits broad lytic activity against a national panel of 100 diverse MDR P. aeruginosa clinical isolates. In Aim 2, we will determine whether the combination of this P. aeruginosa-targeting phage cocktail and P. aeruginosa-targeting antibiotics results in superior and more sustained in vitro killing than either agent alone. Successful completion of these aims will establish a phage-antibiotic combination therapy that can advance in preclinical development and be used in an eventual clinical trial. The project will also directly inform the treatment of critically ill patients who cannot wait for a trial but could still benefit from receiving phage therapy under compassionate use.

NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY. Precise tissue- and temporally- specific manipulation of gene expression has driven mechanistic studies across many different model organisms. Bimodal expression systems such as the Q-system from N. crassa and the GAL4-system from S. cerevisiae are key genetic tools for elucidating gene function and cellular properties. These systems were introduced and optimized in Drosophila melanogaster, contributing to groundbreaking discoveries in embryonic development, animal growth, physiology, metabolism, and neuroscience, and have had a significant impact in the understanding of human biology, in both health and disease. Using CRISPR/Cas-9 technology, the Q-system (the QF2 driver and QUAS reporters) has been successfully introduced to other insects with major impact on human health, such as Aedes and Anopheles mosquitoes. Additionally, it has been applied to vertebrate model systems including the zebrafish Danio rerio. In contrast, while the GAL4 system, has been used in zebrafish, its transfer to mosquitoes has been unsuccessful due to cell toxicity. However, even the Q-system poses a number of limitations, including toxicity and the lack of an effective suppressor that functions independently of chemical compounds. In his application, the Q-system will be re-engineered to remedy these drawbacks by incorporating temperature-sensitive self-splicing intein modules (INTts), tested for efficacy in D. melanogaster and transferred to the zebrafish Danio rerio. Inteins are self-splicing endopeptidases embedded within proteins found in bacteria and unicellular eucaryotes (e.g., yeast), with the enigmatic property of excising themselves from pre-proteins, leading to the generation of a functional protein. Remarkably, inteins can be inserted into foreign proteins, where they self-splice as in their normal host protein. The experimental strategy leverages temperature-sensitive self-splicing inteins that have been validated in S. cerevisiae to self-splice at temperatures up to 270 C in foreign proteins. Specifically, inteins with permissive and restrictive setpoints between 15 and 300 C, compatible with growth and development of insects and fish, will be integrated into the DNA binding domain of QF2 (QF2_ INTts) and the protein interaction domain of QS (QS_ INTts), to disrupt their function when retained at restrictive temperature (24 to 300 C). When kept at permissive set points (17 to 230 C), intein removal via self-splicing activates QF and QS. Transgenic Drosophila will be tested for functionality of QF2_ INTts and QS_ INTts using QUAS-GFP reporter genes at different temperature. Genes encoding validated QF2_ INTts will be conferred to plasmids for D. rerio transgenic fish, tested for functionality using QUAS-GFP reporters. These new tools provide a much-needed temporal control element for the Q-system, making it invaluable for the research community to analyze gene and cell function relevant to human health.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus of significant public health concern. To date there are no effective licensed antiviral treatments or a vaccine. Therefore, elucidating the molecular biology of these viruses and the interactions with the host cell are foundational to identifying and developing effective treatment options. The single-stranded positive-sense RNA genome of ZIKV mimics a cellular mRNA. Specifically, the viral RNA encodes a single open reading frame, has structured untranslated regions (UTRs) adjacent to the open reading frame, and contains a N5’-methyl guanosine cap. Unlike mRNAs however, flaviviruses lack a poly(A) tail. From a multiple sequence alignment of all mosquito-borne flaviviruses we identified conserved regions containing 3-6 tandem adenosines in the 3’ UTR. These A-rich regions are localized in single-stranded regions within and between the XRN-1 resistant pseudoknots (xrRNA), dumbbell and 3’ stem loop (3’SL) RNA structures. In preliminary experiments we investigated the role of the A-rich region between xrRNA2 and the pseudo- dumbbell RNA structure (pre-pseudo/Y-dumbbell). Specifically, we generated three different mutations in a ZIKV Renilla luciferase reporter replicon and infectious clone. These mutants revealed that the pre-YDB A-rich region had a role in translation in both mammalian and mosquito cell lines. Different mass spectrometry studies have shown that the cellular poly(A) binding protein (PABP) interacts with the ZIKV 3’ UTR. Additionally, PABP was previously shown to interact with a region in the dengue virus 3’ UTR that harbors an A-rich motif. In preliminary studies we find that depletion of PABP1 decreased ZIKV, but not cellular, protein levels and viral titers without affecting cell viability. We therefore hypothesize that A-rich regions in the ZIKV 3’ UTR function to recruit cellular RNA binding proteins such as PABP1 to promote distinct steps in the virus infectious cycle. In Aim 1 we will mutate the A-rich regions in the infectious clone and a subgenomic luciferase reporter replicon to investigate the function of select A-rich regions on translation, replication, and viral fitness in mammalian and mosquito cells. In Aim 2, we will investigate the role of PABP1 on ZIKV gene expression and determine if PABP1 and other cellular RNA binding proteins bind A-rich regions in the ZIKV 3’ UTR. Overall, this study will advance our understanding of how flavivirus 3’ UTRs interact with the host to promote distinct steps in the infectious cycle in two vastly different hosts. Understanding how specific sequences in RNA genome function could lead to the therapeutic advancement namely the development of an attenuated vaccine ZIKV strain. Moreover, defining similar and unique RNA-protein interactions between mammalian and mosquito hosts could inform future vector control strategies.

PRODUCTION DISTRIBUTION COMPANIES INC

Electrical Systems and Lighting and Components and Accessories and Supplies

NYS Department of Corrections and Community Supervision

The major goal of the education program is to ensure that every incarcerated individual who leaves the system possesses a High School Equivalency diploma (HSE). To this end, the Department mandates participation in the education program for all incarcerated individuals who do not have a verified High School diploma or High School Equivalency diploma at reception. Because a High School diploma or High School Equivalency diploma is required for the higher paying inmate jobs, there is an added incentive to obtain it.

National Institutes of Health

Academic-Industrial Partnerships (AIP) to Translate and Validate In Vivo Imaging Systems (R01 Clinical Trial Optional)

University of Oregon Libraries

In the second year of this multi-year project, the Archives of Northwest Folklore will improve access to Oregon Folklife Program (OFP) collections in a project that makes effective use of existing library technologies and programs, notably the Archivists' Toolkit (AT), a free and open-source data management system that facilitates publication of finding aids and catalog records, and Northwest Digital Archives (NWDA), an Orbis Cascade Alliance program that provides access to finding aids through an online database. The collections comprise fieldwork documentation generated by of the OFP, which was located at the Oregon Historical Society (OHS) until 2009, and replaced in 2011 as the state's public folklore organization by the Oregon Folklife Network (OFN), located at the University of Oregon. In this year of the project the Archives will use tools it developed during the first year to minimally reprocess collections, inventory and assess media materials, build a collections database, and publish finding aids and catalog records. The primary goal is to improve public access to Oregon folklife collections.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism in the liver is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against liver steatosis. To this point, several ACLY inhibitors have been developed and tested in preclinical studies, and one that specifically targets hepatic ACLY, bempedoic acid, has been FDA approved to treat high cholesterol. Despite this progress, it is now appreciated that there are multiple enzymatic routes to generate lipogenic acetyl-CoA that can be leveraged in different contexts. Our published studies and preliminary data across cell lines and mouse models suggest these pathways have specialized functions, including the production of bioactive lipids important for PPARα signaling. Furthermore, emerging evidence indicates that ACLY also contributes to lipid metabolism in the liver via regulation of gene expression to impact fatty acid oxidation. The diverse mechanisms through which ACLY and BPA influence lipid homeostasis in the liver remain poorly understood; yet they are key to effectively deploying acetyl-CoA metabolism inhibitors to combat MASLD. In this proposal, we will investigate the role of ACLY in mediating diet-dependent lipid metabolism, applying spatio-temporal lipidomics, flux analysis, and gene expression analysis to explore how ACLY regulates PPARα- dependent gene expression (Aim 1). We will also examine ACLY-independent functions of bempedoic acid to elucidate how this drug reshapes metabolism and circadian PPARα signaling (Aim 2). We will leverage genetic mouse models, in vivo stable isotope tracing, lipidomics, mass spectrometry-imaging, and compartmentalized ACLY expression to dissect these pathways. The long-term impact of this work will be a substantially strengthened understanding of the mechanisms through which acetyl-CoA is produced and used in the liver to regulate lipid metabolism, toward the goal of developing improved strategies to treat MASLD.

NIA - National Institute on Aging

Project Abstract Dementia prevalence in Sub-Saharan Africa is projected to increase by over 300% within the next 25 years as the population aged 60 years and older triples to more than 235 million. Beyond the demographic transition and population growth, a major driver of these increases is the growing burden of communicable and non- communicable diseases, which contributes to disability and adverse brain health outcomes. Currently, there are limited data on Alzheimer's Disease and related dementias to inform healthcare and research policies within resource-strained health systems in SSA. This gap is especially evident in French-speaking African countries (30-40% of SSA), which are critically underrepresented in ADRD research. Indeed, our recent review highlights the cultural, ethnic, linguistic, and socioeconomical challenges to dementia research in this setting. In Cameroon, ADRD mortality has increased by over 130% in 20 years and ADRD represents 12.4% of outpatient neurology consultations. Our prior work highlights the urgent need to develop and validate scalable and accessible assessment tools for ADRD to establish a robust infrastructure to support dementia diagnosis, care, and research nationwide. The growing field of digital cognitive tools offers an innovative opportunity for developing easily accessible and highly accurate neuropsychological tools for cost- and time-efficient case identification. Standardized administration, automated scoring/interpretation, and cross platform integration features can address several challenges and support the development of dementia registries – a valuable resource for dementia research and care. The main objectives of this proposal are to culturally adapt and validate a brief multi-domain digital cognitive assessment tool in Cameroon and to develop and pilot the infrastructure needed for improved dementia care and research. Specifically, we plan to culturally adapt TabCAT-BHA digital cognitive assessment in Cameroon, evaluate demographic effects on performance and generate regression-based norms in a community representative sample of healthy adults in rural and urban areas (Aim 1). Concurrently, we will examine TabCAT-BHA’s diagnostic accuracy to detect mild cognitive impairment (MCI) and dementia in the existing BRAIN Cohort and examine its neuroanatomical validity to domain specific regional patterns of brain atrophy on MRI (Aim 2). Finally, as an exploratory aim, we will determine implementation barriers to cognitive testing and dementia diagnosis in a clinical setting in Cameroon to develop the infrastructure needed for improved dementia care and research (Aim 3). These proposed studies will begin to fill the data gap on dementia research in French-Speaking Sub-Saharan Africa (FS-SSA) and provide the first ever neuroimaging data in people living with dementia in Cameroon and set the stage for more comprehensive dementia studies in FS-SSA. For future research following this proposal, we anticipate that valid digital neuropsychological tools coupled with blood biomarkers that still need validation in this setting, could be a scalable and sustainable path for ADRD research, diagnosis and care (R01 proposal)

PROVAIL

Establish an Assistive Technology Lab, specifically designed to meet the needs of children and youth with disabilities under age 18. Additionally, create a mobile Assistive Technology lab that will include laptops, tablets, portable gaming systems, and adaptive hardware to provide therapeutic support and adaptive solutions to children who receive services out in the community. Host provider trainings.

NHGRI - National Human Genome Research Institute

ABSTRACT DNA methylation (DNAme) is a core layer of epigenetic regulation with central roles in the establishment and maintenance of cellular identity. Methods to profile DNAme at single-cell resolution are needed to elucidate epigenetic networks governing cell state in healthy tissues and understand their dysregulation in disease and aging. However, existing methods for single-cell methylome profiling are highly inaccessible, and no methods to experimentally profile both DNAme and spatial location currently exist. I have developed a novel method for single-cell DNAme profiling that leverages the widely available 10x Single Cell Multiome and NEB EM-seq kits, which I have named droplet-implemented single-cell DNA methylation sequencing (discDNAme). Applied to nuclei isolated from mouse brain, discDNAme recovered ~3,000 high-quality methylomes that clustered into clearly separated neuronal and non-neuronal subtypes and displayed stereotyped patterns of CpG dinucleotide methylation around key genomic features. However, these measurements lack spatial information on the native tissue contexts of profiled cells, and the protocol’s per-cell library size is lower than current gold-standard methods for measuring single-cell DNAme. I propose (1) development of a spatially resolved single-cell DNA methylation technology by combining discDNAme with slide-tags, a platform for spatially resolved single-nucleus RNA- and/or ATAC-seq developed by our group. To integrate slide-tags with discDNAme, I will develop a protocol in which the “spatial barcode oligos” we use to position nuclei are physically separated from genomic DNA prior to unmethylated cytosine conversion, benchmark this technology in the mouse hippocampus, and apply it to study glioblastoma multiforme. I further propose (2) experiments to improve and benchmark my discDNAme technology. I will systematically test various independent approaches to increase library complexity at different steps of the discDNAme protocol, combine these optimizations into a second-generation protocol, and benchmark this against our original protocol and other leading methods for single-cell DNAme profiling. Completion of this proposal will result in (1) the first high-resolution method to measure spatially resolved single- cell methylomes—a major advancement in spatial omics technologies—and (2) an accessible yet capable tool for single-cell DNAme profiling that will open single-cell DNAme studies to the broader single-cell community.

PANORAMIC SOFTWARE INC

Engineering and Research and Technology Based Services

National Science Foundation

The National Science Foundation (NSF) is announcing plans to renew this collection. In accordance with the requirements of the Paperwork Reduction Act of 1995, we are providing the opportunity for public comment on this action. After obtaining and considering public comment, NSF will prepare the submission requesting Office of Management and Budget (OMB) clearance of this collection for no longer than 3 years.

Health and Human Services Department

In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate below, or any other aspect of the ICR.

Health and Human Services Department

In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR.

Health and Human Services Department

In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR.

Veterans Affairs Department

Veterans Benefits Administration, Department of Veterans Affairs (VA), is announcing an opportunity for public comment on the proposed collection of certain information by the agency. Under the Paperwork Reduction Act (PRA) of 1995, Federal agencies are required to publish notice in the Federal Register concerning each proposed collection of information, including each proposed extension of a currently approved collection, and allow 60 days for public comment in response to the notice.

NIA - National Institute on Aging

Project Summary/Abstract The world's population is aging rapidly, and by 2050, the population over 60 years will exceed 2 billion people or 25% of the total global population. Tissue repair is critical for the survival of all organisms. Aging causes a gradual decline in tissue integrity, partly due to a decline in stem cell function, a major hallmark of aging. Due to its accessibility and temporal predictability, cutaneous wound healing provides a valuable model framework to characterize the effects of aging on tissue injury1. Aging disrupts the precisely coordinated immune cell response that orchestrates the three phases of cutaneous wound healing. However, it is unknown whether this disruption is initiated by the aging of the tissue itself or the aging of the immune system. Recently, a breakthrough study showed that the aging immune system or “immunosenescence” precedes and drives organ aging2. Thus, an inference from this concept is that the mechanism by which aging impairs wound healing is largely dependent on how aging impairs the immune system. Our long-term goal is to identify how aging impairs immune cell function and show that we can restore youthful wound healing by reversing immune aging. Hematopoietic stem cells (HSCs) are remarkable cells in our bone marrow that make at least one trillion new blood cells daily. We have shown that HSCs produce all of our circulating immune cells and regulate their gene expression by “epigenetic reprogramming”. We will use sophisticated “single-cell epigenomics,” some of which were developed in our laboratories, to characterize how aging affects the gene expression of individual immune cells and how that expression is regulated by epigenetic modifications. We have three Aims: Aim 1: Determine if aging impairs wound healing by an HSC-Autonomous mechanism. Aim 2: Identify the aging-specific- HSC oxidant stress that drives immune aging and impairs wound healing. Aim 3: Identify the master epigenetic enzyme(s) in aged HSCs that epigenetically reprogram the gene expression of wound macrophages and their cross-talk with fibroblasts and keratinocytes. Once we identify the “master epigenetic enzyme” affected by aging in HSCs that reprograms the gene expression of immune cells, we will reverse the effects of aging on the master epigenetic enzyme to restore youthful wound healing. The fact that the effects are “epigenetic” implies that the effects of aging, at least on the immune system, are reversible and, by proof of principle, would open the door to new molecular therapies to reverse the effects of aging.

NINR - National Institute of Nursing Research

PROJECT SUMMARY There are over 177,000 women detained in U.S. jails and prisons on any day and another 800,000 serving sentences in the community under custodial supervision. About 20% of women with criminal legal system involvement (CLSI) are age 50 or older. Rates of women and older adults have both risen dramatically in recent decades, 700% and 280%, respectively. For many women, incarceration and probation are profoundly stressful experiences, often overlapping with other life circumstances—trauma and abuse, homelessness, substance use, mental illness—that disrupt women's support systems and health services access. Many women who experience CLSI also do so repeatedly, cycling in and out of incarceration and probation over many years. The toll on health can be profound. CLSI is associated with disproportionately high rates of many chronic and infectious diseases and early mortality in women of all ages and is hypothesized to lead to acceleration of aging-related conditions. Most of what we know about the health of older women (age 50 and older) with CLSI is extrapolated from the groups of older men and younger women. We lack an understanding of how CLSI functions as a social determinant for aging-related health in the group, including how much, when, and in conjunction with what other factors over the life course experiences of incarceration and probation contribute. We also know almost nothing about the health in aging attitudes, goals, self-efficacy, and experiences of community-dwelling older women with CLSI. The objective of the Aging-Related Health and Aging Acceleration in Older Women with Criminal Legal System Involvement Study (AGELIS) is to fill critical gaps in our knowledge about how CLSI functions as a life course social determinant and what women with CLSI mean by and want from health in aging. Closing such gaps is crucial in moving the field toward intervention readiness and ultimately improved health outcomes. The specific aims of AGELIS are to (a) establish relationships between the health in aging construct, functional ability, life course factors, and CLSI in older women with CLSI, compared with a matched comparison group in the Health and Retirement Study and (b) characterize attitudes, goals, self-efficacy and experiences of health in aging in older women with CLSI using semi-structured interviews and ethnographic case study. In partnership with a community research team, we will bring results from the two aims together in an integrated model of health in aging with CLSI. AGELIS will provide an empirical and experiential basis for subsequent intervention design and point the way forward for investigation in aging with other groups that experience significant life course stress.

NIA - National Institute on Aging

Abstract Support is requested for a Keystone Symposia conference entitled “Aging: Immune Function and Organ Health,” organized by Drs. Anne Brunet, Eric M. Verdin, Manuel Serrano and P. Eline Slagboom, with scientific programming input from Keystone Symposia. The meeting will take place March 22–25, 2026 at the Fairmont Banff Springs in Banff, Alberta, Canada. Aging is the single largest risk factor for a wide spectrum of chronic diseases and mortality, and the immune system is emerging as a crucial player in regulating the human lifespan. Recent studies have revealed that aging can be influenced by changes in immune function and inflammation, offering new treatment approaches to counter aging and age-related diseases. This Keystone Symposia meeting will bring together an interdisciplinary group of researchers to address the impact of the immune system on organ preservation and organ-organ communication, which are critical for organismal longevity. This meeting will also highlight transformative technologies and discuss how engaging the immune system can create opportunities for therapeutic interventions that benefit human health. This meeting will be held jointly with another Keystone Symposia conference, “Innate Immunity: Diversity in Host Defense and Disease.” This partnership will provide valuable insights into the interconnected role of the immune system in aging, its relation to organ function, and implications for organismal health and disease.

National Institute of Food and Agriculture

Agriculture and Food Research Initiative Strengthening Agricultural Systems

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The mucus layer of the digestive system plays a key role in innate immunity, protecting intestinal epithelium from commensal bacteria, pathogens, and toxins. Goblet cells (GCs), secretory cells residing in the intestinal epithelium, are essential for mucin secretion to form this protective mucus layer and maintain its integrity. Ulcerative colitis (UC) is strongly correlated with a compromised colonic mucus layer and a decrease in the number and function of GCs, eventually resulting in inflammatory flare-ups. Unfortunately, current UC treatments display only limited eƯicacy and high recurrence rates, and mostly target the inflammatory process, without inducing mucosal regeneration. In this proposal, we aim to leverage the powerful regenerative potential of the patient’s own cells by activating colon-resident intestinal stem cells (ISCs) to diƯerentiate into GCs. We hypothesize this will augment mucus secretion and rebuild the broken mucosal barrier, eventually preventing pathogen invasion and the consequent inflammatory cascade. Accordingly, the first aim of our study will include artificial intelligence (AI)-guided identification of small molecules that boost GC diƯerentiation. We plan to build on our expertise in ISC diƯerentiation, combined with leveraging existing large biological datasets, including multi-omics datasets and chemical libraries to identify compounds that stimulate GC diƯerentiation. Our second aim is evaluation of AI-identified compounds in UC murine colon organoids (colonoids), and in colonoids derived from UC patients’ biopsies for identification of the most potent GC inducers in this clinically relevant in-vitro model. Our third aim will be dedicated to assessing the therapeutic impact of the top GC boosting molecules in an acute UC murine model. Our proposed strategy to harness the innate stemness of colonic ISCs is envisioned to result in renewal of the colonic GC pool, enhancement of GC-induced mucus secretion and restoration of the mucus barrier function and its key role in innate immunity. We believe the potent stem-cell boosting molecules identified in this study may eventually be developed into a novel treatment modality to replenish the mucus layer and significantly ameliorate inflammatory flares and related symptoms in UC patients.

Alaska Department of Commerce, Community, and Economic Development (DCCED)

The Village Safe Water program funds design, construction, and improvement of water and sewer systems in rural Alaska communities, addressing critical sanitation infrastructure needs for Alaska Native villages.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY The amygdala is present in all vertebrate animals because it influences common behaviors that pertain to threat assessment in the natural world (as well as fear, pain, and reward). Neuroscience well understands how the amygdala interacts with neocortical, subcortical and midbrain sites. However, potential links between the amygdala and brainstem respiratory control sites remains mysterious. This proposal will address that knowledge gap by examining how the central amygdala exerts inhibitory control over the breathing core oscillator site, the preBötzinger complex (preBötC) of the lower medulla. Output from the amygdala largely depends on GABAergic neurons of its central subdivision (CeA). Rhythmic breathing movements depend inexorably on the preBötC. Therefore, a CepreBötC projection would be inhibitory and therefore potentially able to perturb or stop breathing. That microcircuit might be important. Why? First, perceived threats, like the presence of a predator, cause arousal in conjunction with arrest of locomotion. Sometimes freezing behavior is accompanied by bradycardia and diminished breathing: bradypnea or apnea. Whereas the microcircuits for vigilance, locomotor arrest and bradycardia are well understood, the mechanisms that diminish breathing are unknown. We propose an explanation that involves – at least in part – CeA neurons that directly inhibit the preBötC. Second, SUDEP (sudden unexpected death in epilepsy) may occur when seizures invade the lateral or basolateral amygdala, which connect to the much smaller CeA and cause long-lasting apneas. Seizure-induced apneas suspend oxygen delivery yet paradoxically fail to cause panic, dyspnea or air hunger in human patients. We hypothesize that seizures invading the lateral or basolateral amygdala activate the CeA preBötC inhibitory pathway, which can stop breathing. The first Aim of the project tests the hypothesis that CeA GABAergic neurons project directly to excitatory preBötC neurons by installing Cre-dependent optogenetic proteins in CeA neurons of VgatCre adult mice and studying the biophysical properties of their synaptic drive onto core preBötC neurons in adult brainstem slice preparations. The second Aim tests that hypothesis that CepreBötC inhibitory synapses can transiently diminish and/or stop breathing. In this context, we photostimulate the CeA with a graded range of intensities during breathing behavior in awake intact adult mice to evaluate its ability to perturb and/or fully stop breathing. Although we acknowledge that the Aims are adversely interdependent, the abundant pilot data in support of Aim 1 make it unlikely to fail and thus undercut Aim 2. This project will reveal a heretofore unknown microcircuit between 2 key nuclei: the central amygdala and the preBötC. Their connection may help explain ethological behaviors like threat assessment common to all mammals and SUDEP (rare but fatal), which can be leveraged for treatment and prevention strategies.