Grants

The New York Public Library, Astor, Lenox, and Tilden Foundations

Donnell Media Center

Donner Canadian Foundation

The Donner Canadian Foundation supports public policy research, social services, environment, and international development.

NHLBI - National Heart Lung and Blood Institute

Project Summary Red blood cell (RBC) transfusion is an essential part of the management of sickle cell disease (SCD). The effectiveness of transfusion therapy to treat acute disease complications and prevent chronic disease progression have unique considerations in SCD that are dependent upon post-transfusion RBC survival. For many individuals with SCD who receive acute or chronic transfusions, transfusion survival and thus effectiveness is suboptimal. The NHLBI State of the Science in Transfusion Medicine symposium identified optimization of RBC transfusion outcomes for recipients with SCD as a key clinical and research priority. The proposed research will evaluate the impact of donor and recipient factors on the survival of transfused RBCs in recipients with SCD and will examine mechanisms contributing to RBC clearance in both the recipient and the donor. Based on our preliminary data, we hypothesize that RBC components from donors with G6PD deficiency or with alpha-thalassemia trait will have decreased post-transfusion in vivo survival as compared to normal donor RBCs. We have previously demonstrated that recipients with SCD have a much higher likelihood of receiving transfusion from donors with these RBC conditions that are common among healthy donors with African ancestry. We additionally hypothesize that recipients with past RBC alloimmunization responses will have faster clearance of transfused RBCs via mechanisms of spleen and hepatic phagocytic activity. We propose an experimental, interventional, controlled trial with a paired study design that will allow recipient and donor factors to be assessed independently without confounding. Through large-scale next generation sequencing (NGS) genetic screening of at least 10,000 African American blood donors through LifeSouth Community Blood Centers, we will create a database of eligible blood donors including blood type, RBC minor antigen genotype for matching to recipients, G6PD, and alpha-thalassemia hemoglobinopathy status. Pairs of minor antigen-similar blood donors (G6PD deficiency to normal, and alpha-thalassemia to normal) will be recruited for donation, with transfusion directed to pairs of recipients with SCD (alloimmunized vs. non- alloimmunized). Biotin-labeling will be used to measure post-transfusion RBC survival kinetics. Our aims are to (1) determine differences in post-transfusion survival for RBC components from donors with and without G6PD deficiency or alpha-thalassemia trait, and (2) to determine differences in the clearance of transfused RBCs in recipients with SCD with and without past alloimmunization. We will conduct the project through the Georgia Comprehensive Sickle Cell Center at Emory University-affiliated Grady Memorial Hospital. Our project has the potential to improve the management of RBC transfusion therapy, with focus on tangible areas such as donor screening and selection, and identification of recipients at increased risk of suboptimal transfusion survival and efficacy.

NIDA - National Institute on Drug Abuse

Neurologic complications remain prevalent in nearly 50% of people with HIV (PWH) and persist despite viral suppression with antiretroviral therapy (ART). Though the exact processes mediating HIV neuropathogenesis are not well understood, co-morbidities such as substance use disorders (SUD), which are higher in PWH compared to the general population, exacerbate neuropathogenesis of HIV and worsen outcomes. Multiple substances of misuse are reported to increase HIV replication, induce inflammatory signaling, and amplify neurodegenerative phenotypes. Thus, there is a significant need to understand the intersection between SUD and NeuroHIV to improve longitudinal care and inform the public. The overlapping effects of distinct substances of misuse on HIV pathogenesis in the CNS suggest that a common pathway may be involved through presently undefined mechanisms. All addictive substances increase extracellular dopamine in the central nervous system (CNS), which signals neurons and other nearby glial cells expressing dopamine receptors. Our lab has shown that myeloid cells such as macrophages and microglia, which are major HIV reservoirs in the brain, express dopamine receptors more D1-like receptors (D1 and D5) than D2-like receptors (D2, D3, D4). Treatment of macrophages and microglia with micromolar concentrations of dopamine increased pro-inflammatory signaling, increased viral entry, and potentiated viral secretion in vitro. We recently found that a higher D1-like to D2-like ratio is associated with a more pro-inflammatory response in microglia. Further, we showed that dopamine increases activation of nuclear factor-kappa B (NF-κB) in macrophages, and that inhibition of NF-κB can block the pro-inflammatory effects of dopamine. Together, these data suggest that dopamine-enriched brain regions, such as the cortex and striatum, may be especially vulnerable to HIV and neuroinflammation in PWH and co-morbid addiction through the action of dopamine on microglia. Therefore, the central hypothesis of this proposal is that dopamine D1-like receptor activation promotes HIV infection and NF-κB-mediated inflammation in microglia to worsen neurodegeneration. This hypothesis will be tested using human induced pluripotent stem cell (iPSC)-derived brain human cortical assembloids and several orthogonal assays to explore the dopamine-mediated pathways that modulate HIV neuroimmune pathogenesis. We will use pharmacologic activation of dopamine receptors in cortical assembloids to assess viral kinetics (Aim 1), neuroinflammation (Aim 2), and neuronal degeneration of synapses and dendrites (Aim 3). Together, these studies will significantly advance our understanding of dopamine as an immunomodulatory signaling molecule in the context of substance use and HIV, as well as expand the approaches to studying neuroimmune pharmacology using human micro-physiological systems.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Public health in the US is facing two overlapping epidemics, namely, substance use disorder (SUD) and HIV infection. Methamphetamine (METH) use is steadily rising in the U.S., with one study reporting a 43% increase in past-year usage between 2016 and 2019. Clinically, amphetamines, including METH, are associated with cognitive decline and a variety of psychiatric disorders, including depression, psychosis, and anxiety. METH use is a prominent risk factor for HIV infection and correlates with poor adherence to antiretrovirals and, in turn, with worse response to therapy. HIV infection is associated with neurocognitive and neuropsychiatric deficits, loss of dopaminergic neurons, neuroinflammation, and increased neural oxidative stress. The loss of dopaminergic neurons in HIV infection may play a critical role in interactions with METH, as METH’s biological and psychostimulatory effects are primarily mediated through dopamine. Given the public health impact of the METH use and HIV epidemics, there is a critical need to understand the mechanisms driving concomitant HIV and METH-associated neuropsychiatric disorders. The central hypothesis of this proposal is that METH and HIV infection, individually and in combination, contribute to the development of neuropsychiatric disorders in a sex-specific manner. Mechanistically, we propose that an increase in dopamine-induced neuroexcitation, oxidative stress, and mitochondrial damage are responsible for these effects. To address this hypothesis, we will administer quetiapine to mice infected with ecoHIV, a murine tropic HIV, and/or receiving METH. Quetiapine is an atypical antipsychotic that blocks dopamine D1 and D2 receptors while agonizing serotonin receptors. We will evaluate the effect of quetiapine on the neurocognitive deficits and depressive symptoms (Aim 1), and pro-inflammatory and oxidative changes (Aim 2) observed in my preliminary studies on mice receiving METH and/ or infected with HIV. We anticipate that quetiapine will block the excitotoxic effects of dopaminergic neurons and reduce inflammation and oxidative stress, ameliorating the neurocognitive symptoms induced by HIV and /or METH. Additionally, we anticipate improvement of depressive symptoms through both the reduction of neuroinflammation and quetiapine-induced serotonin agonism. My overarching goal is to address a gap of knowledge in the mechanism of HIV and METH induced neuropsychiatric disorders and neurotoxicity by providing proof of concept that quetiapine, an FDA-approved antipsychotic, can prevent or ameliorate HIV and METH induced neurotoxicity and neuropsychiatric disorders. The data generated from Aims 1 and 2 would provide new insights into the treatment of HIV- and METH-induced neuropsychiatric disorders while also playing a crucial role in my development as a physician-scientist with hopes of working in SUD and infectious diseases.

NIDA - National Institute on Drug Abuse

Substance use disorders (SUDs) have surged in prevalence, with cocaine-related overdose deaths disproportionately affecting marginalized populations. Dysfunctional dopamine (DA) signaling has been tied to SUD, with extensive research into DA signaling within mesocorticolimbic circuits specifically focused on the striatum. However, no FDA-approved pharmacotherapies exist for cocaine use disorder, highlighting the urgent need for novel targets. Recent evidence implicates the ventral hippocampus (vHPC) in drug-seeking behaviors and our lab has validated that the vHPC exhibits dopamine-sensing populations of cells that expression the DA receptor type 1 (D1) and type 2 (D2). My findings reveal that vHPC D2 cells drive reinforcement and voluntary drug taking through mechanisms that remain poorly understood. This K99/R00 proposal aims to elucidate how vHPC D2 neuron activity and molecular signaling contribute to cocaine relapse vulnerability. In Aim 1, I will characterize the activity of vHPC D2 neurons during cocaine intravenous self-administration (IVSA), extinction, and cue-induced reinstatement using one-photon calcium imaging. Chemogenetic manipulation will establish the causal role of these neurons in relapse, testing the hypothesis that their activation predicts and intensifies relapse susceptibility. In Aim 2, I will investigate transcriptomic changes in vHPC D2 neurons following cue-induced reinstatement using single-nucleus RNA sequencing (snRNA-seq). Weighted gene co- expression network analysis (WGCNA) will identify molecular pathways that drive relapse vulnerability, with validation through RNA-scope and behavioral correlation. In Aim 3, I will explore how endocannabinoid (eCB) signaling regulates vHPC D2 neuron activity using CRISPR-mediated knockdown of cannabinoid receptor type 1 (CB1R). These data could reveal distinct cocaine-induced changes in function or transcriptome which could provide insight into potential biomarkers making individuals more susceptible to the reinforcing effects of drugs of abuse, and thus addiction liability. Through these novel findings, we will expand our understanding of how drugs of abuse cause molecular, neural, and circuit changes in the brain to hijack reward circuitry and lead to maladaptive reward processing, cue-outcome associations, and drug seeking/taking behavior characteristic of SUD and potentially reveal new biomarkers that could predict SUD susceptibility.

City of Richmond

Dora Ritzer, LMFT

NYC Department of Cultural Affairs

Dorian Woodwind Foundation, Inc.

NCI - National Cancer Institute

PROJECT SUMMARY Contemporary surgical and systemic therapies for pancreatic ductal adenocarcinoma (PDAC) have limited benefit. Median overall survival at 5 years is only 64% even in those who have complete pathologic response to neoadjuvant chemotherapy. This means most patients have resistant minimal residual dormant disease (MRD) at the time of curative intent surgery. The reason for this MRD is best explained by a cellular dormancy based on solitary PDAC disseminated tumor cell (DTC) analysis in livers of humans and mice. The recurrence of PDAC after combined surgery and chemotherapy provides strong clinical suggestion of a dormancy phenotype in patients with locoregional stages. Despite these clinical observations and due to the apparent aggressive nature of PDAC, the notion of dormancy in PDAC is dubious. Yet, a critical need remains to better understand the phenotype MRD in PDAC which will in turn allow the medical community to leverage this information toward truly innovative therapies. The contribution and mechanistic underpinnings of DTC dormancy in PDAC are poorly described. We have identified two pathways that may provide mechanistic insights into how MRD dormancy proceeds in PDAC and importantly these two pathways have identified therapeutics targets that can be leveraged to improve survival. Two key regulators of the dormancy phenotype have emerged: Nuclear Receptor Subfamily 2 Group F member 1 (NR2F1) and RNA-like ER kinase (PERK) of the integrated stress response. The role of NR2F1 and PERK in PDAC dormancy and the efficacy of targeting these in PDAC is unknown. We hypothesize that metastatic competent PDAC DTCs undergo a dormancy phase that is targetable and may curtail metastatic relapse. We propose to determine whether circulating and disseminated PDAC cells in mice and humans express NR2F1 and activate the PERK pathway. We will also determine whether an agonist of NR2F1 in combination with a PERK inhibitor improves the survival of mice with locoregional PDAC via dormancy induction and dormant DTC killing. This proposed study will confirm NR2F1 and PERK activation as markers for dormancy and survival of PDAC disseminated disease. Also, we will determine whether targeting dormancy pathways impacts survival in PDAC. Expected results will provide the rationale for clinical development of targeting dormancy and improving the survival of people with locoregional PDAC. The rationale and methods proposed represent pilot and feasibility studies to explore the biology of MRD and dormancy in PDAC.

City of Richmond

Dorothy C. Martinez

NIA - National Institute on Aging

PROJECT SUMMARY/ ABSTRACT Amyloid precursor protein (APP) represents a complex therapeutic target in Alzheimer's disease (AD), as its processing generates both toxic amyloid-beta (Aβ) peptides and neuroprotective fragments like soluble APP-α (sAPPα)1. While reducing APP through RNA interference shows preclinical and clinical promise for decreasing Aβ burden2,3, the broader impacts of APP knockdown on essential cellular functions, particularly DNA repair, remain unclear. In this proposal, I aim to investigate the dose dependent and region specific effects of APP reduction on AD pathology and DNA damage in the AppSAA mouse model. My study will utilize chemically modified APP-targeting siRNA administered via intracerebroventricular injection at a low and high dose to examine how varying levels of APP knockdown affect AD pathology and DNA damage in different brain regions. Through innovative techniques including Single-Strand Break mapping using Next-Generation Sequencing (SSiNGLe) and MERSCOPE FISH spatial transcriptomics, I will map DNA damage patterns and gene expression changes across different brain regions. This comprehensive approach will be complemented by behavioral testing and molecular analyses to assess cognitive outcomes and inflammatory responses. I hypothesize that the effects of APP knockdown on DNA damage and AD pathology are dose dependent and region specific, mediated by a balance between Aβ, APP, and sAPPα reduction. While reducing Aβ through APP knockdown may decrease some aspects of AD pathology, the concurrent loss of APP and sAPPα will worsen DNA damage and exacerbate AD pathology, particularly in vulnerable brain regions. The findings from this study will advance our understanding of APP's role in AD pathology and normal brain function, potentially leading to more nuanced therapeutic approaches that consider regional brain vulnerability and the importance of maintaining essential APP functions while reducing toxic Aβ accumulation.

Amt Up 3D

The first annual Double Dutch Divas Clothes & Coat Drive will take place at the Benefit Playground located at 9320 38th Ave S Seattle WA 98118 on October 30, 2021 from 2 to 7pm. The event includes music, healthy snacks, hot coco, tea and lots of fun.

NYC Department of Cultural Affairs

Double Entendre Music Ensemble, Inc.

Town of Lonaconing

Douglas Avenue Drainage

Town of Lonaconing

Douglas Avenue Drainage

Douglas County Museum Foundation

Douglas County Museum Foundation is an active grantmaking foundation based in Roseburg, OR. Focus: general. Contact the foundation directly for current funding opportunities.

City of Richmond

Douglass Kidd

Town of Oakland

Dove Center

Town of Oakland

Dove Center

Town of Oakland

DOVE Center Housing

Town of Oakland

DOVE Center Housing

Transportation Agency

DOVER TOWN OF BETTER ROADS

Washington Headquarters Services

DoW’s Energy, Installations, and Environment Innovation Partners Programs

Queens Museum of Art

Down the Garden Path: Artists' Gardens Since 1960