Grants

National Endowment for the Humanities

A "MORE PERFECT UNION": VOICES OF THE AMERICAN PAST, PRESENT, AND FUTURE [AS WE ENTER A PERIOD OF CELEBRATION AND COMMEMORATION AROUND THE 250TH ANNIVERSARY OF THE DECLARATION OF INDEPENDENCE, MONTGOMERY COUNTY COMMUNITY COLLEGE (MCCC) IS PLANNING A YEAR-LONG PROJECT (A "MORE PERFECT UNION": VOICES OF THE AMERICAN PAST, PRESENT, AND FUTURE) TO SUPPORT PUBLIC ENGAGEMENT, HISTORICAL EDUCATION, AND COMMUNITY PROGRAMMING. WITH THIS PROJECT, WE WILL WORK THROUGH THE HUMANITIES TO FOSTER DEEP UNDERSTANDING OF THE FOUNDING CONCEPTS OF FREEDOM AND INDEPENDENCE, ILLUSTRATE THE RICHNESS OF THE AMERICAN STORY, AND PROMOTE CIVIL DISCOURSE.]

NYC Department of Cultural Affairs

A Better Jamaica, Inc.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Ocular Herpes Simplex Virus 1 (HSV-1) is a leading cause of blindness in the US and results from repeated reactivation of latent virus from reservoirs established in host sensory neurons. Latent HSV-1 reservoirs are created when virions infect neuronal axons and travel by retrograde transport to the sensory neuron. While the latent stage of HSV-1 is dormant and not associated with disease, latent virus presents a significant clinical challenge since virus in those reservoirs can reactivate, replicate, and transmit virus to new hosts. During a reactivation event, limited numbers of latently infected neurons produce infectious virus that is transported to the cornea by anterograde transport. That virus can then be spread to other hosts. Nonetheless, mechanisms that govern initiation and completion of reactivation events are unknown, impairing the development of novel therapeutics that can deplete reservoirs or prevent reactivation then transmission of virus to new people. In our proposed research we have identified cellular elements and viral elements that are required to start and then complete the process of reactivation from neurons. We have combined a new human neuronal platform with novel technology known as Chromosome Conformation Capture circular-sequencing to identify virally encoded chromatin loops that can further be targeted for disruption to prevent HSV reactivation and transmission. These new methods have allowed us to generate a novel and paradigm shifting hypothesis. We hypothesize that the function of chromatin insulators in the HSV-1 genome silences gene expression to establish latency, while the initiation of reactivation from latency ameliorates the chromatin insulator function to allow gene expression and subsequent reactivation. We have designed three aims that will allow us to 1) fully define the mechanisms for how this happens during latency and in reactivation and 2) to develop novel therapeutics in accordance with the strategic priorities of the NIH HSV strategic plan. Our novel therapeutic arm of this proposal combines mechanistic data with treatment of infections in the eye by depletion of viral proteins using rAAV-delivered siRNAs or editing of viral genomes using rAAV-delivered CRISPRs. Collectively, our proposal will leverage mechanisms involved in reactivation with targeting those mechanisms to therapeutically block reactivation or deplete latent reservoirs.

Sail Sand Point

Demand for Sail Sand Point (SSP)'s programming is rapidly increasing. The diverse community of Magnuson Park deserves premier access to the unique asset it has at its back door: waterfront access to Lake Washington. Current boathouse facilities are unsafe, unwelcoming and not fully accessible to all members of our community. SSP seeks to create a welcoming, inclusive, fully ADA accessible and world-class community boating center that will allow more people to experience the mental and physical health benefits of recreating in the outdoors, and to provide safe access and oversight to the lake. After completing an extensive feasibility study (including predesign) and community engagement process, we now seek NMF funds to conduct the next critical steps in our project: site surveys, permitting and tribal and other stakeholder consultation and community outreach.

West Harlem Environmental Action, Inc. (WE ACT for Environmental Justice)

to perform research and ceate a report on“Climate Change-Related Health Impacts in Inwood

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT The proposed project addresses critical gaps in understanding the pathogenesis of progressive supranuclear palsy (PSP), a rare tauopathy characterized by debilitating motor and cognitive impairments. PSP is distinguished by its unique neuropathological features, particularly the widespread involvement of glial cells— astrocytes and oligodendrocytes—alongside neuronal tau pathology. Despite recent advancements, the specific role of glial tau biology in PSP remains poorly understood, and this research aims to uncover the molecular mechanisms driving glial tauopathy in PSP. The study integrates cutting-edge techniques, including genome- wide association studies (GWAS), spatial transcriptomics, and multiplex immunohistochemistry, to explore the genetic, transcriptomic, and cellular factors underlying PSP. Aim 1 will identify novel genetic risk loci by expanding the cohort to include diverse populations, addressing the underrepresentation of non-European ancestries in PSP genetic studies. This expanded cohort will enable the discovery of genetic drivers that have been overlooked in previous studies, facilitating a deeper understanding of the disease's genetic architecture. Aim 2 will utilize spatial transcriptomics to generate high-resolution gene expression maps of tau-positive and tau-negative glial populations in key brain regions such as the primary motor cortex and putamen. These spatial maps will be integrated with hyperphosphorylated tau immunohistochemistry to identify molecular changes linked to tau pathology in both glial and neuronal populations. By exploring these relationships, this aim will uncover the role of glial dysfunction in PSP. Aim 3 will focus on region-specific protein markers of degeneration using immunohistochemistry, examining the expression of key neurodegenerative markers and genetic candidates. This will be done through both case-control and case-only studies to correlate proteinopathies with clinical phenotypes, tau-related pathologies, and genetic findings, providing insights into PSP heterogeneity. Furthermore, this aim will deploy A.I. based algorithms of pathology quantification on whole slide images, an approach that could be leveraged in studies of other primary and secondary tauopathies. The combination of these advanced methodologies will offer new insights into the molecular pathways that drive disease progression, particularly the role of glial cells in tauopathy. Furthermore, the focus on diverse populations will ensure that the findings are globally relevant, advancing diagnostic and therapeutic strategies for PSP and related tauopathies.

NIAID - National Institute of Allergy and Infectious Diseases

Infants are especially susceptible to intracellular pathogens because their immune system is not fully equipped to fight against these microorganisms. As a result, infant infections are a leading cause of mortality, with >1.5 million children dying of infections before 5 years of age in 2022 alone. The current consensus is that before birth, conventional T cells are skewed in favor of T regulatory or T helper (Th) 2 responses, leaving neonates and infants more vulnerable to pathogens cleared by Th1 immunity. Therefore, Vγ9Vδ2 (or simply Vδ 2) T cells, are particularly important in early life, because they are poised to secrete Th1 cytokines even before birth and acquire potent cytotoxic function shortly after birth. Despite their protective role against pathogens, human Vδ2 cells, which are absent in mice, are not well studied in neonates and infants. Our long-term goal is to elucidate their functional heterogeneity because understanding their features in the first few months of life will allow us to harness their properties to protect infants from infections. This task is challenging for many reasons, including the difficulty in obtaining samples from the infants at highest risk of early infections, such as premature babies. Our recent observations, obtained using spectral flow cytometry (SFC) and single cell RNA-seq, converge to show phenotypic and functional heterogeneity of cord blood (CB) Vδ2 cells, with heightened stemness compared to their adult counterpart and a cluster of PD1-hi cells (absent in adults) that may follow a distinct functional program specific for the early life stage. We posit that differences in Vδ2 cell cluster composition at birth have functional consequences and result in improved or decreased antimicrobial activity depending on the composition. The resulting overarching hypothesis is that human neonatal V δ2 lymphocytes exist in heterogenous functional/differentiation states impacting host immune competence in the critical early life window. As a multidisciplinary team of immunologists and computational biologists, we propose to characterize cord blood Vδ2 cells in existing specimens, including samples of premature babies, using state of the art techniques –Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE- seq) and SFC- with the following aims. Aim 1. Evaluate the phenotypic and functional heterogeneity of Vδ2 T cells at birth and in early life in relation to age, with a focus on a unique subset of PD1-hi cells present in cord blood. Aim 2: Assess how the composition of Vδ2 T cells at birth impacts function of these cells at the population level, combining CITE-seq analysis with depletion and transduction experiments. The goal of this proposal is to develop a robust molecular and functional map of a critical subset of innate-like T cells, which will provide a valuable reference for the cellular heterogeneity in the neonatal human immune system and a foundation for future proposals aimed at understanding Vδ2 cell biology in early life.

NIA - National Institute on Aging

ABSTRACT IdenƟfying Alzheimer’s disease (AD) in its presymptomaƟc stage can allow early intervenƟon and improve paƟent care. Crucially, the AD-induced amyloid/tau pathology is not limited to hippocampal insult or memory loss, but also impairs /disrupts funcƟonal connecƟons that integrate sensory inputs in the cortex. As these sensory deficits often precede the decline of cogniƟve funcƟon in AD paƟents, understanding their characterisƟc altered funcƟonal connecƟvity and neural hyperacƟvity patterns early in the AD cascade has the potenƟal to yield new diagnosƟc biomarkers or therapies. Similarly, blood flow decline and endothelial dysfuncƟon posited by the vascular hypothesis of AD remains underexplored. While the availability of transgenic AD mouse models has created a unique platiorm for invesƟgaƟng how AD pathogenesis can disturb the neurovascular unit (NVU), design limitaƟons of imaging hardware, e.g. bulky PET, MR or SPECT, that are not developed/opƟmized to probe AD onset, make it unfeasible to image AD pathogenesis at the spaƟal scale of the NVU. Specifically, AD insults the NVU on mulƟple fronts including neural, vascular/blood flow change that span from neurons to cortex-wide brain acƟvity changes, which are modulated with uneven sleep cycle fragmentaƟon/disrupted circadian rhythms. In contrast, preclinical imaging methods are restricted to short duraƟons (< 2 h) due to anesthesia use when imaging a small animal AD model with a device >1000× in size (e.g. PET), and even the state-of-the-art AD studies assess AD-inflicted NVU change only once in every 1-2 months, which substanƟally under-samples the Ɵme course of AD onset. Moreover, since no two brains age the same, subject-specificity can also mask AD-related NVU changes when imaged intermittently. Therefore, new imaging technologies that can generate large neuroimaging datasets and covering mulƟple temporal (days-months), spaƟal (neurons-whole cortex), and modal (neural-vascular) scales are needed to characterize the “funcƟonal fingerprints” of cortex-wide NVU disrupƟon during AD onset. Therefore, we are proposing the development of NeuroCube, which is a miniaturized microscope that will enable mulƟmodal, cortex-wide in vivo imaging >30 days during AD onset in mice. Unlike extant microscopes that lack capacity for long-term operaƟon (<3 h), we will use 3D-prinƟng and fabricate NeuroCube as a robust unit for longitudinal imaging amidst the harsh, jolty condiƟons in an animal enclosure (Aim 1A). To avoid photobleaching, we will use low-light levels, obtain images at low-signal-to-noise raƟos (SNR)/resoluƟon (50 µm), and recover high-SNR/resoluƟon (10 µm) images via a deep learning (DL) backed generaƟve adversarial network (GAN) (Aim 1B). To limit oversized data volumes, we will image in 1-min bursts (0.75 GB) per hour, and curate an imaging dataset that characterize cortex-wide changes of AD, together with gender/age-matched controls (Aim 2). We believe that The NeuroCube and publicly shared in vivo AD datasets will become a vital new tool for the broad AD research community. Moreover, NeuroCubes could be widely useful for interrogaƟng cortex-bound dysfuncƟon in aging and other brain disease.

Upstate Films Limited

A Documentary Approach to History & Literature

NSF

Researchers who study human diseases or test new drugs often use microfluidic devices that contain embedded cells that mimic the behavior of specific organs. The usual approach is to make a change in the cells’ environment and observe changes in the health of the cells. This project will expand that approach by finding ways to control the health of the cells as their environment changes. The project will create an “organ-on-a-controller” system that controls the health and function of human liver cells called hepatocytes. The system will integrate three components: 1) miniature sensors that monitor multiple vital signs of the hepatocytes in real-time, such as protein production and metabolite levels; 2) a computer model that learns how the cells respond to different drugs or nutrients; and 3) an intelligent control system that uses this knowledge to automatically adjust the input to the cells so that a particular cellular health state and function can be achieved. This approach will keep cells healthy and will guide unhealthy cells from a diseased state, such as fatty liver disease, back toward a healthy one. The technology will create a powerful tool that can accelerate the discovery of safer and more effective drugs, advance personalized medicine, reduce the need for animal testing, and provide a deeper understanding of complex chronic diseases. Results will help advance new concepts in biotechnology and advanced biomanufacturing. A fundamental gap exists in our ability to dynamically control complex biological systems. Current in vitro microphysiological systems (“organs-on-chips”) are largely open-loop, precluding the active regulation of cellular function based on real-time feedback. This project aims to address this knowledge gap by creating a first-of-its-kind “organ-on-a-controller” platform that integrates multiplexed biosensing, predictive modeling, and adaptive closed-loop control to actively steer cellular function. Using primary human hepatocytes as a biologically relevant model system, this project will design an integrated microfluidic platform for the simultaneous, real-time measurement of key secreted factors and intracellular reporters of transcription factor activity. Our approach will provide a continuous, multi-parameter view of the cellular state with high temporal accuracy. Further, a library of predictive mathematical models (transfer functions) will be developed that describe the dynamic input-output relationships of hepatocytes in response to metabolic and inflammatory stimuli. A sophisticated model predictive control will be implemented and validated to actively maintain hepatocyte homeostasis under inflammatory challenge and steer cells from a disease state toward a healthy phenotype. By closing the loop between sensing and actuation, the platform will be inherently adaptive, learning from cellular responses to account for biological variability and perturbation. 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.

Jenny Gilbert (Friends of Mount Auburn Cemetary)

A Glimpse Beyond

Sustainable South Bronx

A Greener NYC

Harlem Dowling-West Side Center for Children & Family Services

Construction of a 10-story building with 60 affordable rental units including 12 studio units set aside for youth aging out of foster care and veterans on the 9th and 10th floors. The cellar will consists of 16,000 square feet of program and administrati

NIA - National Institute on Aging

Summary/Abstract Vascular pathology has been identified as a critical driver of Alzheimer’s disease. This proposal aims to establish a human induced pluripotent stem cell (iPSC)-derived model to study the impact of genetic and environmental factors on the development of Alzheimer’s disease-related vascular pathology. Most Alzheimer’s disease patients have cerebral amyloid angiopathy (CAA), the symptoms of which include build-up of amyloid around vessels, cerebral hemorrhages, microbleeds, and inflammation. Studies in multiple mouse models of Alzheimer’s disease have demonstrated that hemopoietic-derived brain-resident microglia and circulating monocytes and perivascular macrophages can be protective against CAA. The APOE44 genotype is the strongest genetic risk factor for Alzheimer’s disease and CAA. Despite the clear interplay between Alzheimer’s disease, CAA, and APOE genotype, the molecular mechanisms underlying the vascular changes are not fully understood. These observations motivate us to create a model using human cells to study the underlying mechanisms of microglia- vascular interactions in cells of different APOE genotypes. In prior published studies, we created a 3D human iPSC-derived vascular model in a hydrogel scaffold. It undergoes vasculogenic and angiogenic events and forms a model plexus (the VAMP model). We showed that the VAMP model can be built inside a microfluidic device to enable regulatable perfusion, mimicking blood flow. We have advanced the model by incorporating microglia (VAMP-MG) to reflect the key cell-cell interactions in CAA better. The work proposed in two specific aims will increase the utility of the VAMP-MG model in five significant ways: We will 1) build the model from a recently established collection of APOE44 versus APOE33 isogenic iPSC lines to incorporate genetic risk factors; 2) incorporate live reporters to monitor the activation states of microglia and vascular cells in real-time; 3) create the VAMP-MG model in microfluidic chips to achieve perfusable vasculature; 4) flow human plasma from Alzheimer’s disease, aged-matched healthy, or young healthy donors through the vessels to improve modeling of disease-relevant environmental factors; 5) use Ribo-Tag technology to identify transcriptomic changes in the vascular endothelial cells and the microglia. The model will be deeply characterized and validated at cellular and molecular levels. Alzheimer’s disease-relevant phenotypes, including amyloid deposition and clearance, A secretion, and inflammatory factor production, will be assessed. We will compare transcriptomic data collected from the model to published human Alzheimer’s disease brain versus healthy control brain transcriptomic data, including single nuclear RNA-seq datasets. Completing the proposed work will enhance our ability to study vascular and microglial responses to inflammatory signals in real time, generate transcriptomic data at cell type levels, and establish APOE44 versus APOE33 phenotypes in microglia-vascular models to a new level of complexity. In the future, this VAMP-MG model can potentially define key genetic and environmental factors that exacerbate or alleviate Alzheimer’s disease-vascular phenotypes.

NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Regulatory T cells (Tregs) dominantly suppress effector T cells, serving as a living therapeutic agent for immunological diseases such as type I diabetes and multiple sclerosis. However, Tregs exhibit a plastic fate at inflammatory conditions characterized by the loss of lineage identity and the acquisition of effector function, which compromises their efficacy. Furthermore, human Tregs cannot be reliably sorted at high purity by surface markers, because conventional T cells transiently upregulate Foxp3 expression upon activation. The presence of contaminating effector T cells would exacerbate inflammation. Technically, retroviral or lentiviral systems, which are widely employed for engineering Tregs, are susceptible to integration site-related effects known as position effects, resulting in substantial variations in gene expression levels. These factors pose challenges for modifying Tregs with enhanced performance for research and therapeutic applications. Therefore, expressing antigen-specific receptors or booster genes in Treg samples presents significant uncertainties. To address this issue, we hypothesize that tethering the Treg master regulator Foxp3 to genes of interest will generate Tregs with high lineage fidelity and robust regulatory function. In preliminary experiments, we began testing this hypothesis. We creatively combined CRISPR/Cas9 genome editing with bacteriophage integration system to insert genes of interest into the 3’ untranslated region (3’-UTR) of the endogenous Foxp3 gene. We leveraged CRISPR/Cas9 genome editing to first insert a landing pad attP site at Foxp3 3’-UTR and subsequently performed site-specific insertion of genes of interest via the attP-attB integration system. We validated this strat- egy in experimental mice and generated knock-in strains bearing Tregs with three representative features, demonstrating the feasibility of our approach. Our method surpasses ectopic Foxp3 expression via retroviral or lentiviral systems in preventing Treg fate loss. The latter cannot convert contaminating conventional T cells into fully functional Tregs, and Foxp3 expression is significantly influenced by the insertion sites. Based on preliminary results, we propose to rigorously test our hypothesis. We will establish a versatile platform to engineer Tregs by expressing genes of interest under the control of endogenous Foxp3 gene via its 5’-UTR or 3’-UTR. This will be first tested in murine Tregs through genome editing in germline. Subsequently, we will extend our approach to human primary Tregs and develop protocols for inserting genes into Foxp3 5’- UTR or 3’-UTR via sequential CRISPR/Cas9- and integrase-mediated insertions. Successful completion of our study will establish an innovative method to engineer Tregs with high lineage fidelity and robust expression of modifying genes, thereby minimizing the consequences of transdifferentiation of Tregs into disease-causing ef- fector T cells or of empowering contaminating conventional T cells. Tregs engineered through this approach will serve as a reliable source for both basic research and translational applications.

Redhouse Arts Center Inc

A Minimum of 24 Performances of 2 Productions

Musica Sacra

a New Birth of Freedom

NIA - National Institute on Aging

Project Summary/Abstract Epidemiological data on Alzheimer’s disease (AD) paint a bleak picture for American society, with the death toll from the disease surpassing that from breast cancer and prostate cancer combined. As the most common cause of dementia, AD afflicts about 7 million Americans as of 2024 and will affect 13 million Americans by 2050. The earliest neuropathology of AD is often the extracellular deposits of Amyloid-beta (Aβ) peptides. If not removed efficiently, Aβ causes synaptic dysfunction and starts to aggregate into plaques, which in turn deform neuronal processes, activate glial cells, and induce inflammation. Recent research has established Aquaporin 4 (AQP4), an astrocyte-specific water channel protein, as a key regulator of Aβ. The mechanism is debated: some researchers argue AQP4 facilitates Aβ removal, while others suggest it helps sequester plaques to minimize neuronal harm. Nonetheless, there is widespread agreement on AQP4's critical role in AD. Recently, we detected an isoform of AQP4, termed AQP4X, and showed that it facilitates the clearance of Aβ peptides and the remodeling of plaques. AQP4X arises from a rare phenomenon called ‘translational readthrough’, where about 20% of the translating ribosomes continue beyond the stop codon, generating an extended isoform of the protein. Unlike the normal-length isoforms of AQP4, which are located away from blood vessels, the extended AQP4X is found in specialized astrocytic projections called ‘endfeet’ that surround blood vessels. To investigate AQP4X in AD, we have developed a loss-of-function mouse (Aqp4No_X, extra stops added to abolish readthrough) and a gain-of-function mouse (Aqp4All_X, stop mutated to sense for constitutive readthrough). When crossed to an AD model (APP/PS1), Aqp4No_X shows impaired Aβ clearance and Aqp4All_X shows enhanced clearance, indicating the importance of AQP4X in Aβ removal. AQP4X may function through the glymphatic system, a pathway thought to involve perivascular AQP4 and the cerebrospinal fluid flow in the brain and remove Aβ from the interstitial fluid during sleep. Unfortunately, in AD, the perivascular pool of AQP4 is altered, and the glymphatic system is compromised. In this proposal, we test the hypothesis that AQP4X is a critical modulator of astrocytes’ response in AD pathology. Aim 1 focuses on identifying pathways relevant to AQP4X function, including the glymphatic pathway, meningeal lymphatics, and circadian rhythms, using techniques such as cerebrospinal fluid tracing and MRI. Aim 2 characterizes the effect of AQP4X on Aβ plaque morphology by quantifying changes in Aβ fibrillation, dystrophic neurites, astrocyte hypertrophy, and microglia activation. Finally, Aim 3 seeks to characterize the effect of Aβ plaques on AQP4X and astrocyte endfeet through biochemical, imaging, and endfoot-specific translational profiling. Overall, our proposal will illuminate the role of Aqp4 readthrough in AD pathology and may establish the phenomenon as a potential therapeutic approach to enhance perivascular AQP4 and to mitigate AD pathology.

NINDS - National Institute of Neurological Disorders and Stroke

Our long-standing goal is to understand how the brain resolves competing needs to determine optimal survival behavior. In this project we ask the question, can circuits activated in different need states suppress the activity of neurons that signal chronic pain? Thus, the experiments outlined will monitor and manipulate neural circuits that reduce chronic pain during competing need states. We focus on the lateral parabrachial nucleus (lPBN), which integrates ascending nociceptive information from the spinal cord with competing survival information. The activity of lPBN neurons is amplified in multiple injury models and activity of PBN neurons correlates with behavioral measures or responses to inflammatory or neuropathic pain. Our ongoing studies indicate that the lPBN receives a dense innervation from neuropeptide Y (NPY) neurons in the arcuate nucleus (that contributes to hunger, ARC), the subparafascilular nucleus (that contributes to fear, SFP), and the ventral periaqueductal grey (that contribute to thirst, vPAG). We show that hunger, thirst, and fear reduce stimulus-evoked activity of lPBNY1 neurons. Importantly, we find that blocking signaling at Npy1r (Y1) receptors in lPBN prevents the ability of hunger, thirst, and fear to reduce behavioral signs of neuropathic pain. This provides the premise for an overarching conceptual framework that Y1-expressing lPBN neurons (lPBNY1) serve as a hub for the integration of multiple needs states with chronic pain. Our research will define the neural inputs that underlie how internal needs (hunger and thirst) and external threats (fear) evoke the release of NPY (Aim 1A) that reverses the hyper-responsiveness of lPBNY1 neurons to sensory stimulation in mouse models of early inflammatory pain, latent sensitization models of chronic inflammatory pain, and nerve injury models of neuropathic pain (Aim 1B). We will use Y1 receptor pharmacology and mouse genetics to definitively demonstrate the cellular target of NPY in the lPBN (Aim 2) and will determine the functional role of each NPY input from the ARC, SPF, and PAG in mediating pain-response behaviors and negative affect associated with chronic inflammatory and neuropathic pain (Aim 3). These will be the first studies to implement assays of NPY release, microendoscopy lPBNY1 recordings, and conditioned place aversion to explore the neural circuits that determine how multiple needs engage distinct, previously unstudied NPY-expressing neurons to suppress chronic pain. Taken together, our experiments will chart the endogenous neural network that modulates the transmission of pain signals through the brain. Ultimately, these studies will reveal important insights into how the brain ranks and responds to competing survival needs in a dynamic environment.

NIA - National Institute on Aging

SUMMARY The prevalence of Alzheimer’s disease (AD), the most common form of dementia, is expected to triple and reach 13 million in the United States by the year 2050. Despite the public health burden of dementia on an aging population, the etiology of AD is still not well-understood. The interplay between the human virome—the total collection of viruses in and on the human body—and host immunity is linked to complex diseases, including AD. Evidence suggests that viral infectious pathogens, such as certain herpesviruses, promote the development of AD. However, methodological limitations of the relevant epidemiologic studies include: 1) reverse causality due to cross-sectional or retrospective case-control study design or consideration of viral infections in elderly participants; 2) underdiagnoses of infections due to detection of clinically apparent infections only; 3) confounding due to unmeasured infections; 4) lack of consideration of joint or interacting effects of multiple infections; and 5) lack of consideration of potential intermediate phenotypes, such as changes in brain and cognitive health, AD-related biomarkers, and DNA methylation patterns related to accelerated aging. The limitations of these studies render interpretation of their findings difficult, presenting an important research gap we propose to address. Recently developed high-throughput methods enable detection of immune responses to all human viruses. However, no studies conducted comprehensive analysis of antiviral antibodies in human sera for AD-related outcomes. We propose a prospective study that uses three prospective cohorts to identify viral infections associated with brain health, cognition declines, and the risk of AD later in life. We will use VirScan, a revolutionary new technology that uses bacteriophage immunoprecipitation sequencing (PhIP-Seq) for comprehensive serologic profiling of exposure history to all known human viruses. Our pilot work shows viral signatures are stable over time, supporting one-time measurement for long-term analysis. Our prospective case- control study of AD nested in the NYU Women’s Health Study (NYUWHS), a prospective cohort of 14,273 women (ages 35–65) who were enrolled between 1985–1991 and donated blood samples at baseline, will assess both: 1) responses to viral infections in relation to AD risk, and 2) whether viral infections are associated with epigenetic age acceleration and AD-related biomarkers. We will use the Cognitive Reserve (CR) study and the Reference Ability Neural Network (RANN) study, which share 529 healthy participants recruited since 2011 across the adult lifespan, to assess responses to viral infections in relation to longitudinal averages and changes in AD biomarkers, as well as brain and cognitive health measured using magnetic resonance imaging and neuropsychological tests. Our findings promise to discover emerging risk factors for AD, improve risk stratification, direct earlier intervention, and open new areas for prevention.

NYC Department of Cultural Affairs

A Public Space Literary Projects, Inc.

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.

U.S. National Science Foundation

A Science of Science Approach to Analyzing and Innovating the Biomedical Research Enterprise

Josephine County

A Street Building Petroleum Cleanup Project