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NIH

Project Summary Background and Innovation: Glucagon has long been recognized as an insulin counterregulatory hormone. However, more recent studies have revealed that it also activates glucagon-like peptide-1 receptors (GLP1R) on beta cells to enhance glucose-dependent insulin secretion. Harnessing glucagon for diabetes therapy has been challenging because of its opposing hyperglycemic and hypoglycemic effects in the liver and islet. Remarkably, we have discovered a transcriptional network controlled by BCL6 in the liver which causes a unique form of selective glucagon resistance and confers favorable anti-diabetic effects in both the liver and islet. Our first aim will elucidate the impact of BCL6 on glucagon action and metabolism in the liver. Our second aim will determine the inter-organ ramifications of this liver pathway on islet signaling and insulin secretion. Finally, in our third aim we will test a liver specific Bcl6 knockdown as a therapeutic for type 2 diabetes mellitus. Our study will elucidate this previously unknown liver pathway using a broad combination of biochemical assays, epigenetic and gene expression analysis, and physiologic testing with unique mouse models and primary cells, including both gain- and combinatorial loss-of-function genetic strategies to reveal interorgan communication. Further, we will use state-of-the-art hepatocyte-directed antisense oligonucleotides (ASOs) for preclinical testing to establish the benefits of targeting BCL6 for diabetes and obesity therapy. Collectively, these experiments will provide deep mechanistic and physiologic understanding of glucagon and therapeutic manipulation of glucagon signaling, setting the stage for clinical development and testing of analogous hepatocyte-directed therapy for humans. Significance and Impact to Veterans Healthcare: Type 2 diabetes mellitus afflicts 25% of Veterans, and hyperglycemia and diabetes-related complications remain inadequately controlled with current therapies. Our findings will elucidate a new target for treating type 2 diabetes mellitus and obesity-related disease. Exploiting this target will enable therapies to leverage both the benefits of glucagon blockade in the liver and glucagon agonism in the islet to improve glycemic control. Moreover, we will establish the efficacy of targeted nucleic acid-based therapy to specifically exploit the liver BCL6 pathway for therapy of type 2 diabetes mellitus in pre-clinical models. Path to translation/implementation: The work in this proposal will be foundational in establishing BCL6 as a new target for diabetes. We will test antisense oligonucleotides targeted specifically to hepatocyte BCL6 in mice. Success in our pre-clinical model can then be advanced for human translation by adapting the antisense oligonucleotides to knockdown the human BCL6 ortholog for future clinical testing in humans with type 2 diabetes mellitus.

Lexington Arts & Cultural Council

Project and operating grants for arts organizations and individual artists from Lexington Arts & Cultural Council. Supports visual, performing, literary, and media arts.

Velocity Dance Center

A vibrant week of outdoor dance performances, large-scale art installations, and LGBTQ+-led conversations in Capitol Hill over Labor Day weekend to promote an inclusive understanding of gender, parenting, and queer lineage. Additionally, organizers will host free BIPOC-led queer parent convenings to build community support networks for queer Seattle parents. Queer and trans family resources will be available in person and online to all participants and project attendees.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is the second leading cause of non-AIDS-related mortality among people living with human immunodeficiency virus (HIV) (PLWH). The number of PLWH is continuously growing due to the viral suppression and life-extending benefits of available antiretroviral therapy (ART). However, the PLWH, even on effective ART with undetectable viral loads as well as elite HIV controllers who are ART-naïve and aviremic, exhibit sustained systemic inflammation and accelerated atherogenesis. Accumulated evidence suggests an important role of persistent macrophage (Mɸ) activation in controlled HIV- induced ASCVD and significant transcriptional heterogeneity among Mɸs within atherosclerotic lesions. Moreover, recent research indicates the involvement of Mɸ-derived extracellular vesicles in regulating neighboring non-HIV-infected Mɸ lipid metabolism, phenotype, foam cell formation, and atherogenesis. However, the precise molecular mechanisms linking controlled HIV infection to Mɸ activation and accelerated atherosclerosis remain poorly understood. Our preliminary experiments utilizing an experimental EcoHIV/NDK model, which mimics the physiological conditions of aviremic patients on effective ART, demonstrate increased atherosclerosis following infection. Furthermore, treatment with conditioned media (CM) collected from HIV- infected Mɸs induces expression of leucine-rich repeat-containing GPCR (LGR) 4 at both transcription and translational levels in non-infected murine primary Mɸs. Notably, Lgr4 upregulation induced by HIV-infected Mɸ CM was significantly higher than that promoted by oxidized LDL, a well-known atherogenic agent. Consistently, LGR4 levels are elevated in human atherosclerotic aortic segments compared with non-atherosclerotic tissue, and in atherosclerotic lesional Mɸs of EcoHIV-infected mice. Additionally, CM-treated Mɸs exhibit increased lipid accumulation (foam cell formation), augmented inflammation, and impaired efferocytosis. Nevertheless, the role of Mɸ Lgr4 in regulating HIV-regulated efferocytic potential, inflammation, and atherosclerosis is unknown. Based on these findings, we hypothesize that controlled HIV infection accelerates atherosclerosis via Mɸ LGR4- mediated signaling. This hypothesis will be tested with the two independent specific aims investigating whether (1) LGR4 mediates HIV-regulated Mɸ foam cell formation and efferocytic capacity, and (2) controlled HIV infection contributes to atherosclerosis via Mɸ LGR4-mediated signaling. Myeloid-cell specific Lgr4-deficient mice, an LGR4-signaling inhibitory peptide, unbiased single-cell RNA sequencing, and atherosclerotic lesion analysis will be employed to test the hypothesis. The successful completion of the proposed studies will provide novel insights into the mechanisms governing accelerated atherosclerosis in aviremic PLWH and identify novel therapeutic targets. To ensure the success of the proposed studies, we have assembled a multidisciplinary team comprising a collaborator and consultants, and are well-positioned to have all the required key resources.

NIH

Significance to VA: According to the Centers for Disease Control and Prevention, female infertility is a major health problem and affects about 6-10% percent (~7.5 million) of women at the reproductive age in the United States. The infertility rates for women Veterans is greater than the general population and is also greater than age-matched active duty women. This translates to well over 100,000 female Veterans. The issue of infertility in Veterans is recognized by the recently introduced Veterans Infertility Treatment Act of 2023 (HR 544) requiring VA to furnish infertility care to veterans and their partners. Ovarian senescence begins about age 30 and over the next 10 to 15 years is manifest by infertility and decreased steroid output. Although ovarian aging is a natural physiological process, cessation of ovarian function at midlife increases susceptibility to the development of co- morbidities, such as osteoporosis, which decrease quality of life and increases healthcare burden. There is currently no intervention for infertility or preventing/delaying the cessation of ovarian function, thus, highlighting an unmet need for novel approaches to tackle this problem. Innovation and impact: Innovation lies in the use of aging ovary models: granulosa cells recovered from young and older reproductive aged women and mice. Innovation lies in the context of understanding the actions of hCG in the aging ovary. Innovation is also derived from our ability to obtain and analyze granulosa cells from patients that have good or poor responses to IVF stimulation, which would facilitate patient phenotyping and personalized treatment plans. Innovation lies in the application of state-of-the-art multi-omics approaches, RNA-seq, CUT&RUN, and ATAC-seq, on matched samples to identify differential binding patterns of selected transcription factors and to profile chromatin accessibility between young and advanced reproductive aged women in response to hCG. The approach will identify and test new candidate genes as potential targets to improve fertility. Specific aims: (1) Determine the transcriptional programs in granulosa cells of young and advanced reproductive age mice and women. We hypothesize that key transcriptional regulators (YAP1 and TAZ) are differentially regulated during aging. We also hypothesize that genomic occupation of YAP1 and TAZ is altered in granulosa of patients who are good responders and poor responders to ovarian stimulation for IVF. (2) Identify and determine the role of hCG-responsive, YAP- and TAZ-target genes in granulosa cells of young and advanced reproductive age mice and women. We will test the hypothesis that YAP1-specific and TAZ- specific target genes will have distinct roles in modulating granulosa cell function. Furthermore, we propose that hCG-mediated, TAZ-responsive genes will improve the health and differentiation of aging granulosa cells, whereas hCG-mediated, YAP1-responsive genes will promote proliferation. Methodology: This project makes use of in vivo aging mouse models using granulosa cells recovered from young and older reproductive age women and mice. We will employ multi-omics (CUT&RUN, ATAC-seq, and RNA-seq) on the same samples to determine and validate specific gene targets to improve the diagnosis and treatment of infertility in women. Path to translation/implementation: This study impacts the VA-ORD Translational Pipeline (TP) Stages T0-1, Disease Biology / pathology (Foundational Studies), T0-2, Target Identification, Evaluation & Efficacy (Proof-of-Concept Studies) and T0-3B, Validation of biomarkers in different populations. We anticipate discovering unique differences in the actions of hCG in granulosa cells as a function of age and patient IVF response. This research will identify and validate new targets, which will facilitate patient phenotyping based on patient age and response. Next steps are to employ in vivo preclinical models using small molecule inhibitors to demonstrate efficacy for improvement of ovarian function and fertility.

Lima/Allen County Foundation

Lima/Allen County Foundation ($75M in assets) supports nonprofits in OH through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

National Institutes of Health

The Instrumentation Grant Program for Resource-Limited Institutions supports the purchase of state-of-the-art scientific instruments to enhance the research and educational missions of resource-limited institutions. Requested instruments may support biomedical research and education in basic, translational, biomedically-related behavioral or clinical fields. This is a Notice of Funding Opportunity (NOFO) for a Limited Competition that will invite application(s) from eligible organization(s) to apply. Please see Section III. Eligibility for additional information. In accordance with NIH standard peer-review processes, the application(s) will be peer-reviewed, and only meritorious application(s) will be considered.

National Institutes of Health

The NIGMS Mature Synchrotron Resources for Structural Biology program supports mature technologies at synchrotron facilities that provide biomedical researchers with state-of-the-art X-ray beamlines, hands-on user training, and expert assistance to generate and analyze structural biology data. NIGMS intends to reissue a Notice of Funding Opportunity to continue to support these important national resources. This is a Notice of Funding Opportunity (NOFO) for a Limited Competition that will invite application(s) from eligible organization(s) to apply. Please see Section III. Eligibility for additional information. In accordance with NIH standard peer-review processes, the application(s) will be peer-reviewed, and only meritorious application(s) will be considered.

National Institutes of Health

<p>The NIGMS Mature Synchrotron Resources for Structural Biology program supports mature technologies at synchrotron facilities that provide biomedical researchers with state-of-the-art X-ray beamlines, hands-on user training, and expert assistance to generate and analyze structural biology data. NIGMS intends to reissue a Notice of Funding Opportunity to continue to support these important national resources.&nbsp;</p><p>This is a Notice of Funding Opportunity (NOFO) for a Limited Competition that will invite application(s) from eligible organization(s) to apply. Please see Section III. Eligibility for additional information. In accordance with NIH standard peer-review processes, the application(s) will be peer-reviewed, and only meritorious application(s) will be considered<i>.</i></p><p>&nbsp;</p>

NIEHS - National Institute of Environmental Health Sciences

Lipoprotein-mediated Nanoplastic Uptake and Transport Across the Placenta Project Summary/Abstract: Micro and nanoplastics (MNPs), are increasingly pervasive in our environment. Microplastics are typically defined as plastic particles smaller than 5 millimeters (5mm), while nanoplastics are even smaller, measuring less than 1 micrometer (1 µm) Originating from the degradation of plastic materials entering our landfills, oceans, and water sources, micro and nanoplastics pose significant concerns for human health. Recent research has expanded its focus on investigating the interactions between microplastics and human placenta, with the understanding of the pivotal role that the placenta has in fetal health and development. This study introduces a groundbreaking perspective aimed at addressing the substantial knowledge gap present about how microplastics translocate into placental tissue and the critical role that chylomicrons may have in facilitating this process. The working hypothesis is that chylomicron-mediated microplastic uptake compromises placental barrier function, leading to the accumulation of microplastics within the placenta and ultimately alters barrier function and cellular response. Utilizing state-of-the-art quantitative methods in previous studies, we have established that the average human placenta at full term contains 130ug/g of total plastics, predominantly comprising polyethylene (53%), polyvinylchloride (10%), and nylon (8.7%). The combination of the prior and this proposed study promises to significantly advance our understanding of the intricate interactions of microplastics, placental function, and fetal development. By gaining a broader understanding of the crucial role of chylomicrons in facilitating microplastic uptake and the consequences, thereof, this research will guide how potential mitigation of microplastic contamination may play a role on maternal and fetal health outcomes.

NIGMS - National Institute of General Medical Sciences

This proposal requests funding for a Liquid Chromatography-Mass Spectrometry (LCMS) system to support biomedical research and educational initiatives across East Tennessee State University's Academic Health Science Center. The instrument will primarily serve researchers and students in the Colleges of Medicine and Pharmacy, while remaining accessible to investigators from the Colleges of Public Health and Arts and Sciences. The acquisition of this LCMS system addresses a critical infrastructure gap that emerged in 2022 when the university's previous LCMS instrument became non-functional. From 2009-2022, LCMS capabilities at ETSU facilitated significant research productivity across multiple investigative teams, resulting in over 40 peer-reviewed publications. This research spans an array of biomedical applications including: pharmacokinetic studies of therapeutic drugs and substances of abuse; development of novel drug delivery systems; quantification of endogenous biomarkers in disease states; stability studies of compounded pharmaceuticals; analysis of environmental contaminants; and investigation of lipid mediators in cardiovascular disease. This productivity has been severely hampered by the lack of this essential analytical capability since 2022. Beyond supporting faculty research programs, this instrument will provide exceptional educational opportunities for a broad spectrum of students, including PharmD, MD, PhD, MS, and undergraduate trainees. Hands-on training with sophisticated LCMS technology will equip these learners with specialized analytical skills highly valued in both academic and industrial research settings. This training represents an uncommon opportunity, particularly for undergraduate science students, enhancing their competitiveness for advanced educational programs and future employment. The strategic placement of this instrument within our shared research infrastructure will maximize its impact, supporting ongoing NIH-funded investigations in areas including pharmacokinetics, drug metabolism, natural product chemistry, biomarker discovery, and neonatal abstinence syndrome research. Additionally, the instrument will enable new collaborative research directions that align with institutional priorities in addiction science, infectious disease, and rural health disparities. In summary, this LCMS system will rejuvenate research capabilities that previously flourished at ETSU, while simultaneously enriching the educational experience of our student population in the biomedical sciences.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Antiretroviral therapy (ART) is remarkably successful at preventing AIDS but is unable to cure HIV infection due to a durable pool of latently infected cells carrying integrated HIV provirus. The persistence of this latent reservoir contributes to a growing population of people living with HIV whose lifespans are shortened by non-AIDS co- morbidities of chronic infection and in whom HIV infection can reactivate upon ART interruption. Selective targeting of the latent HIV reservoir is difficult due to the absence of either detectable viral antigens or cell- surface markers that would reveal viral reservoirs to the immune system. Alternative strategies to reactive latent HIV in these cells and promote susceptibility to immune attack are not sufficiently robust to facilitate elimination of an adequate quantity of the reservoir to achieve cure. Latent provirus in ART-treated HIV-1-infected patients highly enriched in a heterogeneous pool of CD4 T cells exhibiting variably elevated expression of sets of cell surface proteins, including programmed cell death-1 (PD-1) and very late antigen-4 (VLA-4). We believe that logic-gated chimeric antigen receptors (CAR) can be developed to facilitate highly selective killing of cells with these combination of markers (AND gate targeting of cells co-expressing PD-1 and VLA-4, for example) while sparing important uninfected immune effector cells with the similar features (NOT gate to prevent killing of CD8+ T cells). This strategy would permit virus-agnostic eradication of sets of cells with defined phenotypic features that encompass most latently infected cells. Such a strategy could be employed in the context of effective ART to shrink the viral reservoir to a level that can be restrained by antiviral immune responses to facilitate drug-free remission. In this proposal, we will build these CAR molecules and test their ability to durably endow human NK cells with highly selective functional activity against discrete subsets of T cells. In addition, we will characterize the expression of the targeted combination of receptors on latently infected tissue T cells. These studies will provide compelling evidence of the feasibility of these logic-controlled CAR regimens and validate a set of target markers in a pre-clinical latency model. These data will facilitate more advanced preclinical testing in non-human primates, humanized mice, and bona fide reservoir cells from people living with HIV.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Advancements in neuroscience, including magnetic resonance imaging (MRI), have significantly improved our understanding of opioid use disorder (OUD) and brain function, yet due to the heterogeneity in the disorder and complexity of the brain, controlled comprehensive approaches in heterogeneous populations are a necessity to characterize individual variability. Here, longitudinal multi-parametric MRI is proposed to assess brain features associated with OUD in genetically heterogeneous stock rats sourced from the NIDA-funded Rat Oxycodone Biobank (U01DA051937), which provides rats with fully characterized genome and addiction-like behaviors, going through a state-of-the-art pipeline with escalation of oxycodone intake following extended access to intravenous oxycodone self-administration. Leveraging features from structural, diffusion, and functional MRI, our investigation seeks to capture the individual differences in the brain, at baseline before oxycodone exposure (Aim 1: pre-existing), and following the oxycodone extended self-administration paradigm during acute withdrawal (12 h) (Aim 2: oxycodone- induced), within the same rats that show vulnerability or resilience to developing oxycodone addiction-like behaviors. We hypothesize that there will be an interaction between the results from both aims. The I/START R03 proposal will allow for the introduction of MRI imaging into the PARC research environment, as a for the PI new, clinically relevant approach, which will complement her current preclinical work with single- cell whole-brain imaging and simplify the translation of the findings for human applications. The collaborative pilot with the Rat Oxycodone Biobank thus aims to set up the basis for larger follow-up studies that will allow for the generation of a heterogeneous, high-quality imaging dataset that will be made publicly available and complement already extensive genomic and behavioral characterization in the same animals. This data will significantly contribute to our understanding of the variable impact of opioids on the brain and individual differences in vulnerability to OUD, providing a unique opportunity to disentangle pre-existing differences from those that are a consequence of exposure to oxycodone. Ultimately, this research seeks to pave the way for improved prevention and personalized treatment strategies, thereby reducing illness and disability associated with OUD.

Louisiana Community Foundation

Louisiana Community Foundation ($100M in assets) supports nonprofits in LA through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

Louisville Arts Commission

Project and operating grants for arts organizations and individual artists from Louisville Arts Commission. Supports visual, performing, literary, and media arts.

Dept of the Army -- Materiel Command

**PLEASE REVIEW FULL SPECIAL NOTICE** Funding Opportunity Title: Low-Cost Chip-Scale Atomic Clock (LC CSAC) Funding Instrument Type: Technology investment agreement The aim of this Special Notice under the ARL BAA (W911NF-17-S-0003), under Grants.gov Opportunity W911NF-17-S-0003-SPECIALNOTICE-LC-CSAC, is to fund a team or multiple teams to design, manufacture, and deliver a battery-powered atomic clock that achieves identical (or better) size, weight, and power (SWaP) and performance to the commercially available chip-scale atomic clock (CSAC) with a selling price goal of < $300/unit in high volume. Precise timing is critical for numerous Army applications such as navigation, communications, surveillance, and synchronization of sensors and systems. Assured PNT solutions currently rely on acquiring GPS signals, which may not be readily available in increasingly contested environments. Commercially available silicon MEMS and quartz oscillators (TCXO, OCXO) are unable to provide GPS holdover in the event of a GPS outage, except for high-end OCXOs that may be considered large and power hungry for certain applications. To ease reliance on GPS, long-holdover clocks with SWaP-C appropriate for various DoD platforms are necessary to enable mission-critical functions even in contested environments. Current high-performance atomic clocks (maser, laser-cooled cesium fountain) serve as standards and are large, expensive, and require regular monitoring and exquisite environmental control. Since the early 2000s, the chip-scale atomic clock (CSAC) has been developed and successfully matured into a commercial product with DARPA and industry investment. While an Army/Air Force/OSD Manufacturing Technology effort further reduced the manufacturing cost1, the current selling price is still prohibitive for high-volume, low-SWaP DoD platforms. There is an opportunity to leverage the many advances in MEMS, photonics, and atomic physics over the past two decades to develop state-of-the-art, high-performance, battery-powered atomic clocks with improved manufacturability, significantly reduced cost, and improved performance. This special notice seeks proposals from one or more for-profit firms in accordance with 32 CFR 37.210. A consortium, led by a for-profit firm, is also encouraged. Points of Contact: Jonathan Hoffman jonathan.e.hoffman.civ@mail.mil Jenna Chan Jenna.f.chan.ctr@mail.mil

Belltown Community Center Super Heroes

Celebrating the Lunar New Year, artists will be featured in a 2-month-long exhibit with accommodating themed workshops tailored at makers, artists, and Asian culture. A gallery showroom at Slip gallery, 2301 1st Avenue, will feature an ongoing exhibition with Asian American artists living in Seattle and the surrounding local area. The gallery will be open regular hours during these months, and the gallery will be open during the Belltown Art Walk on January 13th and February 10th from 6-9PM. This project will be completed by March 31, 2023.

LVMH Foundation

Funds environmental sustainability, biodiversity, and arts through luxury group philanthropy.

Arnault Foundation

Supports arts, culture, education, and community development through luxury industry philanthropy.

M&T Bank Foundation

Supports community revitalization, workforce development, and arts in the Northeast and Mid-Atlantic.

Madison Community Foundation

Madison Community Foundation ($350M in assets) supports nonprofits in WI through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Maine Arts Commission

Arts Learning grants support K-12 schools and educational organizations integrating arts into curricula, bringing teaching artists into classrooms, and building sustainable arts education partnerships throughout Maine.

Maine Arts Commission

The Maine Arts Commission awards project grants to nonprofit organizations for arts programming that increases public access to the arts, supports artists, and strengthens communities through creative engagement across Maine.

Maine Community Foundation — County Programs

Maine Community Foundation — County Programs ($700M in assets) supports nonprofits in ME through grants focused on education, environment, community development, arts. Awards range from $2,000 to $100,000.