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Santa Barbara Foundation

Santa Barbara Foundation ($500M in assets) supports nonprofits in CA through grants focused on education, environment, arts, community development. Awards range from $5,000 to $150,000.

Santa Fe Community Foundation

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

Saskatchewan Arts Board

The Saskatchewan Arts Board provides grants to professional artists and arts organizations for creation, production, and presentation of work across all disciplines.

OD - NIH Office of the Director

Three-dimensional imaging of preclinical and clinical samples to assess the amount, shape and quality of tissues is essential for research studies in musculoskeletal biology, regenerative medicine, and other fields. One established imaging technique for non-destructive assessment of specimens is microcomputed tomography (microCT), which utilizes the differential attenuation of X-rays by various tissues to provide high resolution (0.5 to 10 ìm) 3D images and to facilitate quantification of tissue morphology. MicroCT has been used extensively to characterize bone density and bone morphology, and is an indispensable tool for investigators in a variety of fields, including musculoskeletal biology, developmental biology, fracture healing, organ cross-talk, tissue engineering and regenerative medicine. Advances in imaging technology and contrast agents now allow the use of microCT for characterization of non-mineralized tissues (e.g. cartilage, tendon, & blood vessels), enabling broad usage of this technology. Here we propose to purchase a cabinet, cone beam, ultrahigh-resolution nano/microCT system (ìCT50, Scanco Medical AG). This advanced system acquires images at voxel sizes ranging from 0.5 to 100 ìm and can accommodate sample sizes up to 105 mm in diameter and 120 mm in height. The system is capable of high-throughput imaging due to an integrated automated sample changer, large X-ray detector and powerful computer workstation. The system will benefit a large group of 11 major and 14 other/minor users who have a track record of using microCT to advance their research. These investigators are funded by 23 current NIH research grants from 7 different NIH institutes (NIAMS, NIDDK, NICHD, NIA, NHLBI, NINDS, and NIDCR). The projected usage of the system by NIH-funded investigators is 90% of the accessible use time (AUT, 69% by major users and 21% by other/minor users). The new scanner will be replacing a 17-year-old microCT system that will no longer by supported by the manufacturer due to lack of access to replacement parts (including the x-ray tube, a critical component of the system). Furthermore, the computer workstation required to operate the machine is no longer produced, and any future repairs and service would need to be sourced by a 3rd party vendor. With strong institutional support, this new state-of-the-art nano/microCT system will be embedded in the Translational Imaging and Phenotyping Core, which is part of the NIH P30-funded Center for Musculoskeletal Research. Importantly, the PI has extensive expertise in use of this technology and has successfully operated this imaging core for over a decade. Altogether, the acquisition of a new nano/microCT system via this shared instrumentation grant will have an immediate and sustained benefit to investigators in the greater Boston area and beyond.

OD - NIH Office of the Director

PROJECT SUMMARY/ABSTRACT This application is a shared instrumentation grant from the Analytical Imaging Facility (AIF) at the Albert Einstein College of Medicine to acquire a new, advanced field emission scanning electron microscope (FE-SEM) with the ability to perform serial block-face imaging (SBF-SEM). The AIF supports many investigators at Einstein (143 Principal Investigator Laboratories in 2024), including many NIH funded investigators, by giving them access to state-of-the-art microscopy technologies that enhance cutting edge, collaborative, and multidisciplinary research. Since 2011, the AIF has had a Zeiss scanning electron microscope capable of 3D volume imaging with a total usage of 1987 hours from January 2024 through August 2024. Due to the age of the instrument, we have only been able to have a limited service contract on the microscope since 2023. This means that the vendor no longer guarantees availability of parts as part of the contract. The microscope had a component failure in September 2024 that the vendor has been unable to repair due to inability to obtain replacement parts. To continue to support the ongoing NIH funded biomedical research that relies on scanning electron microscopy, we need to replace the failed instrument with a new FE-SEM that can offer all the functions of our failed current microscope, including secondary electron imaging for fine surface detail as well as the capability of 3D volume reconstruction. For 3D volume imaging, the requested microscope has the capability of serial block face imaging. In this method, the sample surface is imaged, then a thin slice is removed, then the next image is acquired, resulting in the serial acquisition of a z-stack of the sample. The AIF has ongoing 3D volume projects for all the Major Users in this application. New image acquisition has been halted since the microscope has been down for 8 months. During this period, the AIF staff have been concentrating on image analysis of the collected data by developing expertise in segmentation and presentation of 3D models. A new microscope is urgently needed to enable these projects to move forward. Overall, acquisition of this advanced instrument will have a high impact on the NIH-funded biomedical research at Einstein, including the following major and minor user projects: fine structural aspects of atherosclerosis (Dr. Raiscos-Bernal), cardiovascular disease (Dr. Sibinga), spermatogenesis (Dr. Jenny), cellular response of cytotoxic chemotherapy on lymphoid organs (Dr. Karagiannis), autophagy (Dr. Singh), neurodegenerative disease (Dr. Willis) and diabetes (Dr. Santulli). There are also additional four minor user projects and 6+ labs currently using traditional (secondary electron surface imaging) scanning electron microscopy here at Einstein that will benefit from this technology.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary and Abstract for the SEAL (Stopping Eczema and ALlergy) Study Food allergy (FA) is an epidemic among children in the U.S., U.K., and other countries. There is increasing evidence that epicutaneous allergen sensitization through a dysfunctional skin barrier results in allergic responses whereas early consumption of food allergens induces oral tolerance, as described by the dual allergen exposure hypothesis. In the Learning Early About Peanut LEAP and Enquiring About Tolerance (EAT) studies, dry skin and the severity and the duration of eczema or atopic dermatitis (AD) in the 1st year of life were predictors of peanut allergy (PA) and sensitization. In the SEAL study, we aim to intervene very early in a high-risk infant group, as soon they have the earliest onset of dry skin or eczema in the 1st 10 weeks of life, but before they have developed allergies. By reducing the duration and severity of eczema and preventing eczema exacerbations, we aim to prevent epicutaneous allergen sensitization and significantly reduce the incidence of FA. Our primary objective is to test if the combination of trilipid skin emollient use early in life with proactive topical steroids decreases the prevalence of FA compared to controls. We propose a randomized (1:1), controlled trial design for infants with dry skin or eczema (n=750 total) to compare the effect of proactive treatment against a reactive treatment group for the prevention of FA, by reducing dry skin, and the severity and duration of eczema in early infancy. We will test our hypothesis with the following specific aims using world-class clinical research units known for excellent recruitment and retention of patient cohorts, mechanistic testing, and state of the art research. Specific Aim 1: To determine if proactive versus reactive treatment will reduce the occurrence of FA in a prospective, randomized, and controlled intervention trial of infants with eczema. Specific Aim 2: To test whether the skin of children in the proactive treatment will show improved epithelial barrier markers with increased commensal bacteria colonization. Specific Aim 3: To determine whether proactive treatment will be associated with protective immune responses. If the aims are achieved, our proposal will make a clinical impact by providing a new, clinical strategy to prevent the occurrence of FA in young infants that present with the earliest signs of dry skin or eczema.

Show Your Art

This project is an art walk info session series hosted by Sarah Miller of Show Your Art and Art Walk representatives in three neighborhoods in Seattle. The Downtown Art Walk session will be held at Slip Gallery, 2301 1st Ave, the Uptown Art Walk session will be held at Fishbowl Gallery, 424 2nd Ave W Suite #330, and the Wallingford Art Walk session location is yet to be determined. These free in-person sessions will give artists hands-on guidance with navigating the local Art Walk landscape including talking directly to venue owners, Art Walk representatives, and networking opportunities with other artists. Attendees will learn how to approach venues, understand submission criteria, and build visibility among their peers, all while activating and highlighting participating businesses. Each session connects artists with peers, builds neighborhood cultural density, and promotes accessibility within Seattle’s vibrant art ecosystem. This project will be completed by March 31, 2026.

Seattle Community Puppet Day

Seattle Community Puppet day is being coordinated by a collection of Seattle-based puppet artists to welcome visiting puppeteers from across the Pacific Northwest as they attend the Puppeteers of America Pacific Northwest Regional Festival and will partner with them to provide a neighborhood clean-up, free arts and cultural activities for the public, and a local community fair event. Together with members of the public, they will clean up litter over Capitol Hill on Saturday, August 6th 9:30-11:30 a.m. before welcoming the community to a FREE fun-filled community fair at Seattle Central College, 1701 Broadway, at noon. The fair will provide free performances, arts and crafts activities, local tabling, and more! This project will be completed by September 30, 2022.

Seattle Hoodoo Society

Led by the Seattle Hoodoo Society, Altared Roots, and Sacred Community Connection, the Seattle Hoodoo Arts and Culture Festival is Seattle’s first annual no-cost celebration of the African-American healing tradition of Hoodoo and its role in Black culture. Attendees will learn about the tradition, how Hoodoo has served as a tool of survival in the Black community spanning over 400 years, and be immersed in local artists’ expression of this resilience. The festival is on November 15th from 12 - 5 pm at the Yehaw Indigenous Creatives Collective located at 9666 51st Ave S. The festival will feature artists and performers showcasing art rooted in the Hoodoo tradition, healers who will offer traditional services to the community free-of-charge, and workshops that further educate people on this practice and its history. While this event centers the Black community, all are welcome to learn about this rich and vibrant tradition. This project will be completed by 1/31/26.

City of Seattle Department of Neighborhoods

Matching grants for arts, culture, and community building projects in Seattle neighborhoods. Requires community match.

Seattle Repertory Theatre

On December 10, 2021, Seattle Rep's Public Works department will produce a virtual event featuring Lear DeBessonet and Todd Almond?s musical adaptation of THE WINTER'S TALE in collaboration with a group of up to eight community partners. Rooted in the values of equity, imagination, and joy, this project will advance arts equity and provide arts access to communities that have historically been excluded from the arts by using theater as a tool for equity and inclusion. The virtual event will be free and expect to reach at least 2,000 households on both a local and national scale. Project completion date will be February 28, 2022.

Seattle Sister Cities Association

The Sister Cities Signpost is intended to increase awareness of Seattle's Sister City Program and its position as a global city by having a piece of public art that would showcase the names of each of Seattle's Sister Cities. The design includes sign blades made in colors that will blend in with the Seattle sunset while also providing an attractive piece of public art that will be a colorful contrast against our often-grey skies. The anticipated project completion date is December 31, 2025.

NIA - National Institute on Aging

PROJECT SUMMARY. Alzheimer's disease (AD) is characterized not only by progressive memory loss but also by a range of non- cognitive deficits, including sleep disturbances and autonomic dysfunction. Emerging evidence implicates herpes simplex virus type 1 (HSV-1) as a critical environmental trigger that accelerates AD pathology. Our preliminary data demonstrates that HSV-1 preferentially infects the locus coeruleus (LC) and paraventricular nucleus of the hypothalamus (PVN) in both wild-type (WT) and AD mouse model mice—key regulators of non- cognitive functions—to induce early amyloid deposition, tau hyperphosphorylation, and neuroinflammatory responses, ultimately exacerbating AD progression. Furthermore, HSV-1 exacerbates microglia dysfunction and amyloid accumulation in AD mice. These observations raise a critical question: does HSV-1 infection initiate early transcriptional and post-translational changes in the LC and PVN that accelerate physiological and behavioral deficits? In this proposal, we hypothesize that HSV-1 induces Aβ and NFT formation in the LC and PVN, triggering a hyperinflammatory response prior to hippocampal involvement. To test this hypothesis, we will employ an integrated, multidisciplinary approach using advanced spatial transcriptomics and proteomics (via the NanoString GeoMx DSP platform) alongside in vivo electrophysiological (EEG/LFP) and behavioral assays (using FED3 feeding devices). Aim 1 will delineate the spatial and temporal molecular alterations in the LC and PVN following intranasal HSV-1 infection in 3xTg AD mouse models and WT controls. This analysis will focus on the regional accumulation of amyloid and tau pathologies, microglial activation, and associated gene expression changes that precede hippocampal involvement. In Aim 2, we will link these molecular changes to functional outcomes by monitoring disruptions in LC activity, sleep-wake cycles, EEG rhythms, and feeding behavior. This study is innovative in its use of state-of-the-art spatial omics combined with rigorous neurophysiological and behavioral assessments to bridge the gap between molecular pathology and functional deficits in AD. The outcomes are expected to provide critical insights into HSV-1's role in triggering early AD pathogenesis, particularly in non-cognitive domains, and may identify novel targets for early intervention. Ultimately, this research will help reshape our understanding of viral contributions to neurodegenerative processes and inform the development of therapeutic strategies aimed at mitigating both cognitive and non-cognitive symptoms of AD.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Human immunodeficiency virus-1 (HIV-1) remains incurable except in rare cases. The ultimate barrier to sustained remission without continuous antiretroviral therapy (ART) is the HIV-1 reservoir, which remains under-characterized, particularly across individuals who differ by age, sex, and ART history. This submission is for a Mentored Patient-Oriented Research Career Development Award (K23) entitled “Sex Differences in HIV-1 Reservoir- a Multi-omic Approach to Identify Mechanisms of Reservoir Decay”. I am an Assistant Professor at the University of Pittsburgh specializing in HIV medicine and general infectious diseases. I developed this proposal to leverage multi-dimensional platforms to investigate drivers of change in the HIV-1 reservoir over a decade of suppressive ART, with the ultimate goal of identifying new approaches to eliminating the HIV-1 reservoir. It seeks to examine the longitudinal decay patterns of intact proviruses, a robust marker for the HIV-1 reservoir. I am particularly interested in the interaction between age, sex, hormone levels, HIV-1 immune responses, and HIV-1 reservoir dynamics. My preliminary study, supported by the Rustbelt Center for AIDS Research (CFAR) pilot funding, suggests there are distinct patterns of HIV-1 provirus decay and immunological correlates in females compared to males with HIV. Further studies and training are needed to take these preliminary findings to the next level and systematically dissect the chronological, virological, immunological, and hormonal influences of HIV-1 reservoir dynamics. The findings from this proposed study would help identify therapeutic targets for HIV-1 reservoir clearance. To gain the skills necessary to achieve my career goal of becoming an independent translational physician-scientist, I propose this career development plan that includes mentoring from Drs. John Mellors, Charles Rinaldo, and Mark Cameron (primary mentors), along with Drs. Bernard Macatangay, Sharon Riddler, and Nicolas Sluis-Cremer (advisory team). This team represents research leaders across HIV-1 virology, immunology, single-cell sequencing, and systems biology. This project will utilize de-identified data and samples obtained from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study Combined Cohort (MWCCS), a four-decade longitudinal multicenter cohort studying individuals with or at high risk for HIV- 1 infection. Dr. Charles Rinaldo, one of the primary mentors for this project, is also one of the founding scientists of MWCCS. The proposed work will be conducted at the Division of Infectious Diseases at the University of Pittsburgh, Pittsburgh, PA and Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH. Guided by highly supportive mentors who are the top experts in their fields, with unwavering support from my department, I am confident that I will acquire the skillset required to perform cutting-edge translational studies on the HIV-1 reservoir that will lead to innovative approaches to achieve HIV-1 remission. 1

NHLBI - National Heart Lung and Blood Institute

ABSTRACT This proposal requests NHLBI support for the 2026 Scientific Sessions meeting presented by the Council on Basic Cardiovascular Sciences (BCVS) of the American Heart Association (AHA). This meeting has become the “go to” meeting for basic and translational cardiovascular sciences by providing opportunities for established and emerging investigators to present their work and receive constructive feedback. The meeting in 2026 represents the 21st consecutive annual conference. Funding for BCVS Scientific Sessions from National Heart, Lung and Blood Institute (NHLBI) has been secured for 17 of the last 19 years. The BCVS summer conference is entitled “Shaping the Future of Cardiovascular Medicine: Integrating Basic Science Breakthroughs to Clinical Impact”. In 2025, our in-person conference was a rousing success with about 1,000 investigators from around the world. We plan to again hold an in-person meeting in 2026 to help facilitate the careers and networking opportunities for young investigators and support collaborations. The meeting is scheduled for July 13-July 16, 2026 and will begin on a Monday and run through Thursday. The conference will highlight the newest basic and translational cardiovascular research with implications for cardiovascular health and disease. There will be approximately 14 scheduled state-of-the-art sessions that include a mix of established and emerging investigators. The 2026 BCVS keynote address will be given by Dr. Johnathan Epstein, a Robert G. Dunlop Professor, who serves as Dean of Perelman School of Medicine and Executive Vice President of the University of Pennsylvania for the Health System. There are specific sessions for early career scientists, including two early career sessions, an Early Career Keynote Lecture, and the Outstanding Early Career Investigator Award Competition. We will host special sessions for networking including interactions with journal editors and staff. We will also include a Networking Breakfast to support scientists. This R13 proposal is designed to provide support to young investigators to enable their participation in the meeting as presenters either in oral or poster format. The primary organizers are Drs. Farah Sheikh and Jennifer Davis. The Program Committee (11 members) includes the past program co-chair and leadership from across the US drawn from the many disciplines encompassed by BCVS. The AHA will continue to provide its outstanding administrative support with dedicated staff for the logistics of the conference. We fully anticipate that this team will coordinate an exceptional 2026 BCVS conference.

National Institutes of Health

This Notice of Funding Opportunity (NOFO) announces the restructured Shared Instrumentation Grant (SIG) Program that consolidates three existing shared-use instrumentation programs, i.e., the Shared Instrumentation Grant program, the High-End Instrumentation Grant program, and the Basic Instrumentation Grant program. The NOFO invites applications from groups of NIH-supported investigators to purchase or upgrade a single state-of-the-art commercially available instrument or an integrated instrumentation system. The instruments purchased through the SIG Program are required to be optimally shared among the users to ensure efficient and cost-effective research operations, enable rigorous and reproducible measurements, and encourage collaborative research and benefit broad research communities at large. The minimum award is $300,000. There is no cap on the total cost of the instrument; however, the maximum award is $5,000,000. Cost sharing is required for premium instruments or special use instruments.

Jackson Place Business Association

The independent businesses, storefronts, art studios, live/ work BIPOC, LGBTQ+ creative spaces make our neighborhood a more vibrant and desirable place to live and work. Together with our residents, people who work in the area and new visitors who discover our unique neighborhood we hope to grow a stronger sense of community through the installation of holiday lighting on our small dead-end street called the Hiawatha Arts & Business Corridor located on the 800 block of Hiawatha Place South. This project will contribute to better public safety by creating a more attractive and interesting area for visitors to discover, explore, and feel safe walking their pets at night, returning to the neighborhood through public transportation, or patronizing the storefronts or community space in the center of the block. This project will be completed by April 29, 2022.

Sikh Foundation International

Supports Sikh studies programs at universities, Sikh art preservation, and educational materials about Sikh heritage and culture.

Sikh Foundation International

Supports Sikh studies at universities, art preservation, and educational materials about Sikh heritage and culture worldwide.

Sioux Falls Area Community Foundation

Sioux Falls Area Community Foundation ($400M in assets) supports nonprofits in SD through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

NIA - National Institute on Aging

Project Summary Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of hyaline cartilage lining articular joints. A critical challenge for OA management is the development of an effective treatment that reverses cartilage damage. Our previous work indicates the existence of adult skeletal stem cells (SSCs) in postnatal cartilage. These SSCs are dormant yet can potentially repair damaged cartilage when stimulated by surgical procedures such as Microfracture (MF). While MF typically results in the formation of inferior fibrocartilage, we have demonstrated that MF-activated tissue-resident SSCs can be expanded and directed towards the formation of healthy chondrocytes and hyaline cartilage to regenerate full-thickness cartilage defects by pharmacologically modulating SSC activity and the microenvironment surrounding them. This method we termed Growth-factor Enhanced Microfracture (GEM). Our published studies and preliminary data demonstrate that GEM works well in young animals but is less effective in aged mice. Our data supported by recent findings of others further suggest that FGF7 (Fibroblast Growth Factor 7) expression in the SSC lineage is induced by an inflammatory aged and osteoarthritic bone marrow niche, which leads to pro-fibrotic lineage-skewing resulting in cartilage loss. We now build on additional preliminary results showing that direct and indirect blockade of FGF7 during GEM can reinstate stem cell-based cartilage formation in joints of aged and OA mice. The gained insights from the proposed study will help us to develop strategies to efficiently apply GEM even in impaired settings with a cellular microenvironment less conducive to articular cartilage regeneration. To that end, we are elucidating the cellular dynamics and molecular mechanisms that underlie SSC mediated cartilage repair. In Aim 1, we will expand our preliminary findings to confirm and mechanistically dissect how inhibiting FGF7 locally during GEM in aged and osteoarthritic mice can promote hyaline cartilage formation. In Aim 2, we will determine if epigenetic rewiring of local SSCs by a novel therapeutic compound is sufficient to overcome age-related impairments of GEM mediated cartilage regeneration. Our experiments will use state-of-the-art structural and functional readouts at the tissue level as well as latest technology to unravel cellular and molecular changes at the single cell level to assess regenerative properties and provide new biological insights into OA. Our team brings together expertise in skeletal stem cell biology, in-depth basic science and clinical knowledge of OA as well as bioengineering competency. We are using cutting-edge methods to pursue hypothesis-driven questions aimed at unlocking endogenous stem cells for cartilage repair. By taking advantage of a therapeutic window to skew local MF-activated SSC fate we want to generate new cartilage for the resurfacing of OA joints independent of age and disease state. Eventually, we wish to translate these preclinical studies.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY: SKIN-TARGETED METAL-ORGANIC FRAMEWORK-BASED SUBUNIT VACCINES Driven by their affordability, manufacturability, and safety benefits over traditional vaccines, subunit antigens are an important component of modern vaccinology. However, they exhibit poor immunogenicity and efficacy, and thus, new and rational strategies are required to improve their immunogenicity and efficacy. We propose a novel skin immunization platform (SIP) to address the limitations of vaccine development with subunit antigens. Our innovative and globally deployable SIP leverages emerging vaccine technologies, including (1) metal-organic framework (MOF) nanovaccine constructs; (2) a clinically de-risked adjuvant, and (3) needle-free, thermostable, and self-applied microneedle arrays (MNAs), as well as highly immunoresponsive skin niche for the development of effective and accessible subunit vaccines. The central hypothesis of our project is that in situ harnessing of the immunologically rich milieu of skin with our SIP in a spatially and temporally controlled manner will drive the generation of robust, durable antigen-specific humoral and cellular responses in a well-tolerated manner. Our SIP is engineered in the form of rapidly separable MNAs (rsMNAs) that consist of high-quality obelisk-shaped microneedles comprising dissolving polymer matrix tips loaded with MOF vaccine constructs and non-dissolvable stems with filleted bases attached to the backing layer. Unlike traditional MNAs that require relatively longer wear times (minutes), our rsMNA design, which is enabled by the unique ability of biodegradable MOFs in protecting vaccine components against denaturing organic solvents needed to form non-dissolvable stems of microneedles, facilitates the implantation of MOF vaccines into the skin in less than 10 s via shear force. Our SIP offers the superior vaccine delivery and immunogenicity characteristics compared to needle-and-syringe (N&S) vaccines and conventional MNA-based vaccines. As such, our SIP unlocks the true potential of the skin immune system for improved cutaneous vaccination strategies with subunit antigens. Ultimately, this project will yield a rapidly translatable SIP that will provide unparalleled flexibility and efficacy for vaccination with subunit antigens, which is unattainable with the state-of-the-art immunization platforms.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY: The currently available antiretrovirals can effectively control HIV-1 replication and thus prevent disease pro- gression to AIDS. Such antiretroviral treatment (ART), however, cannot eradicate the infection. Latently infect- ed cells persist through ART and, if ART is stopped, will lead to rebound of viral replications within weeks. In- fected individuals therefore need to take medications for the entire life span and consequently suffer from drug resistance as well as severe side effects including cardiovascular complications, metabolic disorders, and neu- rocognitive damage. Novel antiretrovirals that could eliminate HIV-1 infection and cure the disease is thus high- ly desired. It is believed that HIV cure could be possibly achieved through empowering host immune cells to recognize and kill HIV-1-infected cells. One significant barrier here, however, is that HIV-1 has evolved mech- anisms that enable infected cells to evade host immunity. A key player here is the HIV-1 Nef protein. Nef is a master regulator of HIV-1 immune evasion. By downregulating MHC-I from the surface of the host cell, Nef dis- rupts host cell’s antigen presentation, which then allows the infected cell to evade immune surveillance by host cytotoxic T lymphocytes (CTLs). Nef also downregulates CD4 from the cell surface; this benefits the infected cell in several ways including evading killing by natural killer (NK) cells through antibody-dependent cellular cytotoxicity (ADCC). Inhibition of these Nef functions should revitalize both CTLs and NK cells, empowering them to find and kill HIV-1 infected cells. This project is aimed at developing such inhibitors and thus overcome the barrier of viral immune evasion to facilitate the cure. Four in vitro assays have been developed and opti- mized for screening small molecule libraries to find inhibitors. Two assays, orthogonal to each other, are both capable of identifying inhibitors that can block Nef’s activity on MHC-I and CTLs (having two orthogonal assays here allows cross-validation of hits to ensure discovery of true inhibitors). Another two assays, also orthogonal to each other, are capable of finding inhibitors that can block Nef’s activity on CD4 and ADCC. These assays have been tested in a proof-of-concept screen against a medium-sized compound library. All four assays per- formed excellently, indicating their suitability for high-throughput screening. A hit compound has been found from this modest screen and was subsequently validated through concentration-dependent studies in vitro. Building on these promising results, we now propose to carry out—using our developed assays and the estab- lished workflow—large-scale library screens to identify inhibitors against the two targeted Nef functions (Aim 1). We will then use both in vitro and cell-based assays to characterize inhibitors and identify those with out- standing potency and efficacy (Aim 2). We will also solve high-resolution structures of inhibitor-Nef complexes and then use the structural information obtained to guide chemical derivatization of lead compounds (Aim 3). Upon completion of the project, we will obtain potent inhibitors of Nef-mediated immune evasion, ready for fur- ther development into real-world antiretrovirals to facilitate HIV cure.

Columbia City Theater Group

Local artists, activists, and educators will collaborate to offer Seattle youth the opportunity to build community through production of a theatrical play, film festival, graphic-novel adaptation, and accompanying resources. These creative projects will build community and engage youth in social justice through the rich tradition of storytelling and the exploration of race, socioeconomics, education, and the arts.