Grants

Dept. of the Army -- USAMRAA

DOD Defense Health Agency (DHA) Research & Development FY23-FY27 BROAD AGENCY ANNOUNCEMENT for Extramural Medical Research

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Koob and colleagues have postulated that an imbalance between neurotransmitters in the brain stress and anti-stress systems drives negative reinforcement and compulsive alcohol use in alcohol use disorder (AUD). Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP), is one such neurotransmitter in the brain that regulates stress and resilience in animal models of addiction. N/OFQ, when infused in the brain, increases corticosterone, adrenocorticotropic hormone, and corticotrophin- releasing factor (CRF), all components of the hypothalamic-pituitary-adrenal axis that regulate stress responses. CRF infusions have also been shown to upregulate NOP, presumably to enhance N/OFQ signaling, in brain regions that regulate stress. Surprisingly, both NOP agonists and antagonists show therapeutic effects in rodent models of AUD. However, rodent models do not clarify which, if any, subtype of AUD subjects (e.g., heavy drinking) will benefit from treatment with NOP agonists Vs. antagonists. Previous [11C]NOP-1A PET studies conducted by our group in humans with AUD have demonstrated lower binding (VT) to NOP receptors in heavy relative to nonheavy drinking AUD subjects. In these AUD PET studies, lower NOP receptors also predicted relapse to alcohol in a 12-week contingency management protocol that incentivized subjects with money to abstain. Assuming lower NOP receptors reflect higher N/OFQ levels; these results suggest that increased N/OFQ signaling in heavy drinkers contributes to their inability to abstain during treatment. Blocking excessive N/OFQ signaling with a NOP antagonist drug (LY2940094) has also been shown to decrease heavy drinking days and increase abstinent days in AUD subjects in clinical trials. An emerging view in the field is that a hyperactive N/OFQ-NOP receptor system, in response to increases in CRF transmission, induces hyperkatifeia, negative reinforcement, and relapse in AUD. To investigate CRF X NOP interactions in humans, we designed a PET experiment to measure [11C]NOP-1A VT before and after an intravenous (IV) hydrocortisone challenge in healthy controls (HC). Hydrocortisone administration led to a 10 to 15% increase in [11C]NOP-1A VT in brain regions, including the amygdala. Increased NOP measured in response to cortisol, and by extension, CRF, in this paradigm reflects an individual’s ability to enhance N/OFQ transmission during stress. Here, we propose to use this novel imaging paradigm to compare hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) in the amygdala (and secondary reward regions) in heavy drinking AUD subjects Vs. HC. We hypothesize that hydrocortisone-induced increases in [11C]NOP-1A binding (DVT) will be larger in heavy drinking AUD relative to HC (aim 1), and this will predict relapse to alcohol (aim 2). Such a result will support the presence of a hyperactive NOP receptor system in response to increases in cortisol/CRF during conditions such as stress, chronic pain, etc., promoting relapse in heavy drinking AUD subjects.

NIA - National Institute on Aging

Project Summary/Abstract In Greek mythology, Mnemosyne is the Titan goddess of memory. The idea of memory as Titan likely stems from our cultural understanding of how memory helps form the core of a person’s personality, experience, and perspective. This is also one reason that loss of memory can be so devastating--it is especially prevalent amongst people who suffer from Alzheimer’s disease and other dementias; this neurodegenerative disease strips people of much of what they were. We have discovered a new player in the brain’s ability to retain memory: the protein LRP1 (low-density lipoprotein receptor related protein 1). We think understanding LRP1 will lead to exciting and novel insights into how patients with Alzheimer’s disease lose their memory. The brain has some capacity to regenerate due to a small population of neural stem cells. These neural stem cells are also fundamental in allowing the brain to retain memory. In Alzheimer’s disease and related dementias, patients lose neural stem cells. We have discovered that if we remove LRP1 from neural stem cells in adult mice, the mice show signs of significant memory impairment and altered neurogenesis, similar to mouse models of Alzheimer’s disease. Others have discovered that LRP1 plays a role in Alzheimer’s disease by interacting with proteins we already know cause disease in the brain, including amyloid beta, ApoE4, and most recently tau. Extracellular tau is particularly interesting due to its pathological, prion-like spread in the brain, which is facilitated by LRP1. What is not yet understood is whether extracellular tau can exert any physiological role, particularly on those processes which regulate neurogenesis to impact hippocampal memory function. This exploratory/developmental grant is designed to test the hypothesis that tau modulates neurogenesis through LRP1 in adult-born granule neurons. Our preliminary studies find that loss of LRP1 in adult-born hippocampal neurons cause phenotypes similar to those of tau knockout mice, including increased mature, adult- born granule neurons in LRP1 knockout cells and increased survival of developing neurons. Mature LRP1 knockout neurons displayed reduced dendritic branching. In the hippocampus, we expect that increases in extracellular tau alters neurogenesis to influence learning and memory via LRP1. Aim 1 will test the LRP1- dependent effects of extracellular tau on development of adult-born hippocampal neurons. Aim 2 will test whether rescuing LRP1 in adult-born hippocampal neurons rescues dendritic complexity in a tau- dependent manner. We will test our hypotheses via a combination of in vitro cell culture approaches with in vivo histological tests in our mouse model that allows knockout of LRP1 in adult neural stem cells, combined with tau knockout or infusion. We expect to leverage existing tools to enhance understanding of LRP1 in neurogenesis and Alzheimer’s disease, and by extension reduce the burden of this disease.

NSF

Animals all over the world are being pressured to move to new habitats at higher latitudes and higher elevations. While many species are successfully moving towards the poles, relatively few are migrating upslope as fast as they need to. One intuitive but untested explanation for this mismatch could be that high-elevation habitats do not provide enough oxygen to support lowland species’ essential activities (e.g. foraging, mating, evading predators). As a model organism for testing this hypothesis, the project will use dragonflies, whose extreme aerobic requirements during flight should make them especially sensitive to the low oxygen at high elevations. By combining an integrative set of lab experiments with a large-scale field inventory of dragonfly species in the Rocky Mountains, the research will advance our understanding of the barriers that animals face when dispersing into a new environment. This project will further help scientists and land managers make better forecasts for the kinds of traits that animal species will need in order to establish populations at higher elevations. This work will also provide training opportunities for the next generation of scientists and produce a report about the statuses of dragonfly species on public lands in Colorado. The goal of this project is to test if low oxygen prevents species from dispersing to higher elevations. Using dragonflies as a model, the proposed approach will explore this putative physiological barrier across three aims: (1) Test if low oxygen inhibits locomotor performance of dispersing adults during any elevational range shift or only during shifts into the most extreme elevations. A replicated transplant experiment in the Rocky Mountains and Appalachian Mountains will assess how flight performance is affected when the putative constraint of low oxygen is relaxed at high elevations and imposed at low elevations. (2) Test if the species that are most tolerant of low oxygen have shifted upslope the farthest in the last 20 years. A field survey of the Rocky Mountains will determine how species’ elevational limits have changed in Colorado since the early 2000s, and lab assays will assess if these shifts are related to the species’ physiological characteristics. (3) Test if a species’ ability to engage in aerobically demanding activities is impeded more by lower oxygen or warmer temperature. A respirometry experiment will evaluate how aerobic scope will be affected by the future conditions in species’ current elevations versus the atmospheric conditions at the elevations where they are expected to migrate. Overall, by integrating respirometry, whole-organism performance trials, and biogeography, this research will test a potentially overlooked physiological constraint on species’ elevational range shifts. 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 Intestinal failure (IF) occurs when patients are not able to maintain sufficient hydration or nutrition through oral intake alone due to either inadequate length of bowel (“short gut syndrome”) or inadequate function of the bowel. Intestinal transplantation (ITx) is the definitive therapy for patients with IF who have no possibility of enteral independence and the only remaining therapy once parenteral nutrition fails, but its use is limited by high rates of rejection that necessitate increased levels of immunosuppression, predisposing patients to infections, malignancy, and graft-versus-host disease. Therefore, identifying strategies to avoid ITx rejection, especially by developing donor-specific tolerance in an otherwise immunocompetent host, would make ITx a more attractive therapeutic option for patients with IF and might also be a useful strategy for other types of transplantation. Based on our pre-clinical studies, matching donor/recipient major histocompatibility complex (MHC) class II appears to be a promising strategy. We developed a swine orthotopic ITx model based on our clinical ITx protocol and found that, unlike fully-MHC-mismatched pairs, sharing only a portion of a single class II allele decreased rejection and promoted the development of regulatory T cells (Tregs) and donor-specific hyporesponsiveness in the graft, while greater MHC sharing extended these findings to the peripheral blood and permitted durable mixed chimerism (donor cells in the recipient’s blood) in a small pilot experiment cohort. We therefore hypothesize that selectively matching donor/recipient MHC class II, which is not currently performed routinely, promotes longer rejection-free survival (RFS) of ITx grafts by minimizing rejection through expansion of Tregs, possibly in a dose-dependent fashion. If our hypothesis is validated, class II sharing could be used to improve ITx outcomes since living donors are usually first-degree relatives and share at least half of their class II alleles with the recipient, and it is also feasible to achieve class II sharing in deceased donor transplantation because some class II alleles exist at high frequency in the general population. Based on our in vitro data, we additionally hypothesize that the mechanism by which class II sharing promotes regulatory tolerance is through linked suppression. If supported by our data, this too would present an opportunity since this immunological principle could be applicable to all forms of transplantation, not just ITx. Therefore, the overall goal of this project is to test our hypothesis regarding the clinical advantages of class II sharing and to evaluate the immunological mechanism by which this occurs. Thousands of patients would benefit from ITx if outcomes were improved, and our prior data have generated a hypothesis for improving immunological outcomes. These data support pursuing further investigation, which we are uniquely poised to perform due to our novel human and large animal models and our ability to perform the proposed mechanistic analysis. Our prior human and swine studies demonstrate the feasibility of our proposed Aims.

NSF

Seagrasses are marine flowering plants that provide important benefits, including protection from shoreline erosion and creating habitats that support ecologically and commercially important marine species. They are often infected with a slime-mold pathogen that creates dark brown lesions on the plants, called eelgrass wasting disease. The effects of this disease range from the die-off of entire meadows to smaller declines in plant growth, with the reasons for this variation generally unknown. The disease typically peaks during the summer when temperatures are warmer, highlighting the relationship between temperature and disease. However, plants from different populations vary in how they grow and survive at different temperatures, suggesting that plants that are adapted to cold versus warmer water may show different temperature-dependent responses to the disease. Furthermore, when plants survive the infection, it is unknown if previous exposure to disease influences future plant response to disease in beneficial or harmful ways. In this project, the investigators are testing how plants adapted to different temperatures respond to disease, and how the effects of disease on eelgrass change depending on temperature and the plant’s history of disease. Results will be useful to local, state, and federal agencies, as well as non-profit organizations that manage and restore critical eelgrass habitat. The study is helping identify characteristics of populations that may make them more or less resistant to the combined effects of disease and other stressors, allowing prioritization of intervention efforts. It is providing support for graduate students and a post-doctoral scientist, engaging undergraduate students in research through immersive classes, and expanding and supporting research opportunities and mentorship of students from a local two-year college. Infectious diseases are increasing globally, causing significant declines in the abundance of ecologically and commercially important species. Disease is often associated with warmer temperatures, suggesting that diseases are often thermally dependent. However, disease dynamics are difficult to predict because host populations vary in their response and recovery to infection. Theory suggests that thermal mismatch between hosts and broadly-tolerant pathogens can drive disease dynamics: warm-adapted hosts are more likely to be diseased in colder conditions, and cold-adapted hosts are more likely to show disease in warm conditions. How prior disease exposure modifies a host’s thermal critical limits and disease response is important to consider when repeated pathogen exposures exist in species without adaptive immunity. Ultimately, an understanding of how previous disease exposure influences future disease response across populations is needed to predict which populations will be susceptible to outbreaks. To that end, the investigators are using the eelgrass Zostera marina as a model species to test how locally-adapted hosts respond to wasting disease across the range of currently-observed temperatures and whether previous exposure influences host response. Project aims are to: 1) compare disease severity and plant productivity across a gradient of temperatures in the field through both field surveys and reciprocal transplants; 2) determine the thermal performance of host-pathogen interactions of warm and cold-adapted populations in the lab; and 3) determine how carry-over effects associated with disease modify plant responses to future disease attack across temperatures. 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.

East Windsor

Dog Pound Roof Replacement

East Windsor

Dog Pound Upgrades

City of The Dalles

Dog River Pipeline Replacement Project

Citizens for Off-Leash Areas (COLA)

COLA will plan and host a public event to celebrate dogs and their friendship to our families. We will have a doggy costume contest, a special performance by Caspar Babypants, Halloween activities for dogs and kids, and several vendor booths to highlight nonprofits and other canine friendly companies and resources. The event will take place on October 22, 2016 from 11 am to 4 pm at the Bell Street Park and Regrade Off Leash Area, 206 Bell Street.

NYC Department of Cultural Affairs

Doing Art Together, Inc.

Megan Fernandes

Dollhouse Poetry

Dolphin Scholarship Foundation

Dolphin Scholarship Foundation is an active grantmaking foundation based in Virginia Bch, VA. Focus: education. Contact the foundation directly for current funding opportunities.

DECD

Domestic Abuse Services Ctr. @ YWCA

Corrections

Domestic Violence Accountability Program

THE SALVATION ARMY

Healthcare Services

LIFE SPAN

Organizations and Clubs-Civic organizations and associations and movements

FAMILY RESCUE INC

Organizations and Clubs-Civic organizations and associations and movements

Urban Justice Center

Domestic Violence and Empowerment (DoVE) Initiative

City of Willamina

Domestic Water Mains Replacement Project

City of Willamina

Domestic Water Mains Replacement Project

NYC Department of Cultural Affairs

Dominican Collectives Dance Ensemble

Montgomery County MD / State of Maryland

Other Legislative Initiatives

NHLBI - National Heart Lung and Blood Institute

The Don S. Fredrickson Lipid Research Conference (FLRC) brings together scientists and trainees investigating the impact of lipid and lipoprotein metabolism on the development and treatment of Cardiometabolic Disease. The FLRC is named after the late Don S. Fredricks who as the director of the National Heart Institute (now the NHLBI) from 1966 – 1974 and later the NIH, developed the clinical classification for dyslipidemias (Type I-V), described Tangier’s Disease, and made seminal discoveries in lipoprotein metabolism. Most importantly, he trained both basic and clinical scientists and practitioners who have had a tremendous impact on the field of lipoprotein metabolism. Since 2016 the FLRC has employed a rotating institutional host model and has been hosted by the University of Kentucky (’16, ‘17, ’21), Vanderbilt University (’18, ‘23), the University of Cincinnati (’19), Duke University and the University of North Carolina (’22). The FLRC will be hosted by the Medical College of Wisconsin in 2025 and return to UK in 2027. Keynote Lectures at the 2025 Fredrickson conference include Ira Tabas, Columbia University, and David Ginsburg, University of Michigan. The thematic scientific sessions include Genetic determinants of lipids and CVD; Lipoprotein structure and omics; Immune cell lineage/immunity and lipids in CVD; Microvascular, adipose and lipids; Novel perspectives in lipid research; and Lipids in atherothrombosis and hemostasis. The FLRC places a strong emphasis students, fellows, and early career faculty. In accordance with that mission, the agenda also includes additional scientific talks dedicated for trainees, a “Research Blitz” session (90-second presentations), and a judged poster session. By design, the agenda affords every trainee in attendance the opportunity to present their research on stage, network with leaders in the field, and broaden their scope and understanding of research in lipid metabolism and Cardiometabolic Diseases. Our format encourages informal interactions between scientists at all levels, providing an innovative approach to the exchange of ideas and synthesis that will move the field of lipid research forward. The conference will have high impact as the program spans basic science discovery to clinical significance. It is therefore expected that the meeting will provide new insights not only into basic aspects of lipid metabolism, but also how to treat, and ultimately cure, a wide variety of Cardiometabolic Disease states.