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NIDA - National Institute on Drug Abuse

Project Summary Investigating and Addressing Modifiable Factors in the HIV Care Continuum for People with HIV (PWH) affected by Substance Use and Mental Health Social determinants of health like poverty, and unstable housing, combine synergistically with comorbidities like substance use (SU) + mental health (MH) as a syndemic to disproportionately burden disadvantaged populations people living with HIV (PWH). Substance use and mental health comorbidities are associated HIV Continuum of Care Outcomes (HCC) like delayed entry into care, lower retention in care, reduced ART adherence, poor VL suppression, and higher mortality for PWH. For the US to end the HIV epidemic (EHE) by 2030, the underlying mechanisms of SRD- driven health disparities on viral suppression and HCC outcomes among all PWH experiencing substance use and mental health syndemic must be elucidated and addressed. The lack of suitable comprehensive longitudinal data to examine substance use, and mental health impact on dynamic changes in HCC outcomes limits our ability to end the HIV epidemic. Defining and describing the impact of substance use and mental health on HCC outcomes requires examining the complex interactions of sociocultural, economic, environmental, and geographic contexts influencing these interactions. To address the knowledge gaps on modifiable factors related to the intersection between SU+MH, we propose using real-world multiple linked datasets, including enhanced HIV/AIDS surveillance (e-HARS), Electronic Health Records (EHR), Department of Mental Health data, Department of Alcohol and Other Drugs of Abuse (DAODAS) data, corrections data administrative claims, and other relevant public data sources, to investigate the disparities in SU, MH recognition, treatments, and HCC outcomes using data science. We will use qualitative methods to examine interpersonal and intra-individual factors to identify modifiable factors for moderating the effects of the intersection of SU+MH on viral suppression and the HCC. The specific aims are to: 1. Examine and visualize the longitudinal patterns/trends, heterogeneity, and disparities arising from SU on viral suppression and other HCC outcomes among PWH in SC; 2. Determine the interactive effect of SU+MH on viral suppression and other HCC outcomes; and 3. Understand experiences and impact of SU+MH on viral suppression and other HCC outcomes among PWH population in SC using focus group discussions/in-depth interviews.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Neuroprosthetic interfaces provide paralyzed patients increased agency and independence. These intracortical implants interface with cortex at the cellular level, readout neural activity in real-time, and transform this activity into the actuation of computer cursors, robotic prostheses, and speech generators. Recent advances in the software underlying these devices have led to highly accurate brain-computer interfaces (BCIs) for improving health outcomes in patients with severe spinal cord injuries, neurodegenerative diseases, and stroke. However, there are still many fronts that require improvements. Namely, these devices have a learning curve on the order of days to weeks very similar to that of learning a new skill. In addition, even when accurate performance is reached, the natural drift of neural recordings necessitates system recalibrations, which requires the patient to briefly re-learn the new algorithmic parameters. Here, we propose that these learning periods can be reduced by augmenting the neural signaling pathways the brain uses to learn new BCI skills. A structure deep in the brain called the basal forebrain is known to play a strong role in learning new tasks, such as new motor movements. This region extends axons from cholinergic neurons up to cortical regions, where they are extremely active during the learning phase of new tasks, enhancing the local plasticity of cortical circuits. Recently, studies have shown that manipulating these axons can influence learning and task performance. For example, stimulating the vagus nerve can increase cholinergic activity and when timed properly can lead to faster learning rates and more accurate performance on a variety of sensorimotor tasks. In this work, we propose that the cholinergic neurons in the basal forebrain also play a major role in the learning and control of neuroprosthetic interfaces, particularly when these devices are implanted in motor cortex. To investigate this hypothesis, we will use a state-of-the-art combination of multiphoton imaging and transparent electrode arrays to record cholinergic axon activity near the implanted BCI as rodents learn to perform neuroprosthetic skills. In addition, we propose that vagus nerve stimulation can be used to excite cholinergic activity and reinforce neuroprosthetic learning, reducing the training time needed for animals to achieve expert-level control. Importantly, vagus nerve stimulation is an approved human treatment. Therefore, not only will our work reveal a fundamental circuit mechanism critical for BCI control, but our research opens the door to new applications of vagus nerve stimulation for enhancing neuroprosthetic performance in humans.

NIMH - National Institute of Mental Health

Project Summary HIV-1 associated neurocognitive disorders (HAND) affect 15 to 40% of people living with HIV (PWH), despite the use of anti-retroviral therapies (ART). Persistence of HAND in the presence of ART suggests that factors outside of viral replication contribute to neurocognitive impairment. The HIV-1 transactivator of transcription (Tat) is a neurotoxic viral protein that recapitulates cognitive impairment in the absence of viral replication and persists in virally suppressed PWH, likely generated from cellular reservoirs including microglia and astrocytes. Prior studies have separately shown that in the presence of Tat, the microglial transporter xCT is upregulated – increasing extracellular glutamate – and astrocytic EAAT2 is downregulated. Nonetheless, these mechanisms have been demonstrated with varying techniques and agnostic to how Tat expression within cellular reservoirs affects Tat-mediated toxicity and cognitive symptoms of HAND. Thus, we hypothesize that Tat expressed independently from microglia and astrocytes promotes aberrant glutamatergic neurotransmission causing NMDAR dependent excitotoxicity in the prefrontal cortex and cognitive impairment in HAND. In this proposal, we will use lentiviral transduction to model Tat expression from microglia and astrocytes, as the HIV-1 reservoirs of the CNS. We will then assess glutamate toxicity in this model in vitro and in vivo, by evaluating 1) EAAT2 or xCT expression and markers of gliosis [GFAP, Iba1], 2) extracellular glutamate levels in culture supernatants, 3) neuronal NMDA receptor expression and signaling via calcium levels. These outcomes will provide an understanding of how microglia and astrocytes respond to Tat and influence NMDAR- mediated neurotoxicity. To understand how these cell types drive toxicity and cognitive impairment in turn, lentivirus will be injected intracerebrally to prefrontal cortex of Sprague-Dawley rats. Two weeks after surgery, we will assess behavioral and molecular outcomes; or calcium levels in neurons and astrocytes. Animals will undergo testing in novel object recognition, spatial object recognition, and attentional set-shifting tasks, to assess learning and memory and cognitive flexibility. Brain tissue will then be assessed by immunoblot, RT- PCR, and calcium imaging to correlate cognitive impairments with molecular mechanisms; further paralleling the in vitro results to contextualize the contribution of Tat-mediated mechanisms to cognitive impairment. This study will elucidate the role of microglia and astrocytes as separate sources of Tat for their effects on glutamatergic neurotransmission and PFC-mediated cognitive functions. The proposal addresses a significant gap in the literature on microglia as the primary viral reservoir generating Tat, while accounting for the distinct impacts of each cellular reservoir on Tat-mediated glutamate toxicity and cognitive impairment. This will prompt future study into the microglial reservoir, and glutamatergic disease mechanisms that could be refined as therapeutic targets that are clinically relevant to neuropathology in PWH.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY / ABSTRACT A vaccine that elicits broadly neutralizing antibodies (bNAbs) against the Envelope (Env) protein of HIV-1 would be the best approach to end the AIDS epidemic; however, no efficacious vaccine has been developed to date. bNAbs targeting the conserved V3-glycan epitope of Env such as PGT121, 10-1074 and BG18 bind to the conserved GDIR motif of Env and to a key glycan at position N332 (N332 glycan). The absence of the N332 glycan in multiple HIV-1 strains limits the neutralization breadth of these bNAbs to ~60-70%. Based on observations by us and others, we hypothesized that V3-glycan antibodies that do not require the N332-glycan for binding can be elicited and matured into bNAbs by vaccination. We further hypothesized that N332-glycan independent V3-glycan antibodies will have greater neutralization breadth and that immunotherapies combining N332-glycan dependent and independent bNAbs will impose strong restrictions to viral escape, resulting in longer periods of suppressed viremia. To test these hypotheses, we developed WIN332, an Env-based immunogen that lacks the N332-glycan. Immunization with WIN332 in nonhuman primates (NHPs) induced a new class of N332-glycan independent V3-glycan antibodies. Most importantly, WIN332 elicited N332-glycan independent neutralizing antibodies to the V3-glycan epitope as early as three weeks after a single immunization. Our studies established a new classification of V3-glycan antibodies into Type-I (N332-glycan dependent) and Type-II (N332-glycan independent) and presented WIN332 as a promising vaccine candidate to streamline bNAb development (Relano et al, Nat.Immunol. in press). Further supporting our overarching hypothesis and this proposal, now two Type-II human bNAbs that target the V3-glycan epitope in a N332-glycan independent manner, EPTC112 and 007, have been reported, demonstrating that Type-II lineages can develop in humans and are a significant target for vaccine design. In this proposal, we will build on these studies and leverage WIN332 to investigate the new class of Type-II V3-glycan antibodies and its potential as a novel target for vaccine and immunotherapy design. In Aim 1, we will leverage WIN332 as a probe to isolate new Type-II bNAbs and bNAb precursors from infants and adults living with HIV-1 and from healthy donors respectively. We will characterize the newly isolated Type-II bNAbs and evaluate their capacity to increase neutralization coverage and restrict viral escape. In Aim 2, we will use our state-of-the-art methodology to produce new immunoglobulin knockin (Ig KI) mice that express unmutated precursors of human and NHP Type-II bNAbs and use these mice to investigate the maturation pathways of these bNAbs. Through advanced protein engineering approaches, structural studies and assessment in humanized mice, we will design novel vaccination strategies to mature N332-glycan independent lineages. We expect our innovative vision of the V3-glycan epitope will enable the identification and characterization of previously overlooked bNAb lineages of potential clinical value and will result in new immunization protocols to streamline bNAb development.

NCI - National Cancer Institute

Small cell lung cancer (SCLC) is a highly aggressive, recalcitrant neuroendocrine carcinoma associated with a dismal prognosis. Despite recent progress, the molecular mechanisms that promote the development of SCLC remain incompletely delineated and there is an urgent need for refined, more effective therapies. Our long-term goal is to elucidate the chromatin, epigenetic and transcriptional mechanisms that promote and are required for SCLC, and to translate these mechanistic findings to the clinic. We have recently identified recurrent inactivating mutations in genes that encode for subunits of the polybromo-associated BAF (PBAF), a SWI/SNF chromatin remodeling complex. Yet, the functional consequences, underlying mechanisms and therapeutic targets associated with PBAF inactivation are unknown. Our project is based on the following preliminary findings: 1) Genomic analyses of ~1200 SCLC patient samples reveal recurrent loss of function mutations in PBAF. 2) PBAF exerts tumor suppressor functions in cellular models. 3) PBAF-deficiency leads to a marked acceleration of SCLC development and a stark reduction in overall survival. 4) PBAF-deficient SCLC models exhibit increased chromatin accessibility and an upregulation of pro-growth, pro-metastatic gene expression programs. 5) PBAFdeficient SCLCs are reliant on residual SWI/SNF complexes for growth. Altogether, our results pinpoint a critical function for PBAF in SCLC. Our central hypothesis is that PBAF-deficiency promotes SCLC development by altering chromatin structure, transcription factor binding and gene expression programs, and that such alterations lead to the development of SCLCs with unique biological features and therapeutic vulnerabilities. To test these hypotheses, we will pursue the following three aims: 1) Establish the functional importance of PBAF during SCLC initiation, progression, and metastasis. 2) Elucidate the transcriptional and epigenetic mechanisms underlying PBAF-deficient SCLCs. 3) Evaluate SWI/SNF inhibition as a therapeutic strategy for PBAF mutant SCLCs. This project is significant because it focuses on understanding the function of a recurrently mutated chromatin remodeling complex in SCLC and will guide future translational efforts for the most aggressive form of lung cancer. It is conceptually and mechanistically innovative because it leverages the first PBAF-deficient mouse model of SCLC. Our investigations require the use of these innovative animal models to study the functions of PBAF during SCLC initiation, progression and metastasis, which is currently not possible with any other model. While there is no equivalent non-animal alternative that allows us to effectively perform the proposed investigations, the animal studies will be complemented, when suitable, with human centric models such as ex vivo human systems, patient derived xenograft models (PDXs) and human SCLC specimens. Finally, our study is technically innovative as it implements state-of-the-art epigenomic profiling techniques. Collectively, our research will improve the understanding of SCLC biology and reveal new therapeutic avenues for patients.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

SUMMARY Human milk provides nutrients and important non-nutritive factors for infants that promote growth, development, and protection from infection1,2. Therefore, the World Health Organization (WHO) recommends exclusive breastfeeding for 6 months, then combining breastfeeding with solid foods for 18 months3. Lactation disorders reduce breastfeeding rates, and negatively impact both mothers and children. In mothers, lactation disorders influence mood and maternal well-being, while in children, they affect cognitive and socio-emotional development4, and can cause malnutrition, hypernatremia, hypoglycemia, and death5. Moreover, breastfeeding rates are lower in some ethnic minorities, which may partially reflect poor access to lactation consultants and early initiation of infant formula. Lactation disorders that specifically impair milk production and secretion affect about ~40% of breastfeeding mothers, the major phenotypes including: (i) agalactia: complete absence of milk secretion following birth; and (ii) hypogalactia: insufficient volume for optimal infant nutrition6,7. While post-partum stress, obesity, diabetes, and socioeconomic considerations have been associated with hypogalactia, we and others have demonstrated that hypogalactia has an inherited maternal genetic component6,8,9,10. However, the genetic mechanisms responsible for human lactation disorders are mostly unknown and have not yet been extensively investigated. We hypothesize that variations in genes involved in human milk production and secretion underlie disorders of milk production and secretion, and that these variants and genes can be discovered by interrogating genomic and extensive health and metadata from women with lactation disorders cases compared to unaffected female controls. We therefore propose to conduct a comprehensive study on whole exome sequencing (WES) data of lactation disorders patients. We are uniquely positioned to perform the first such study with the largest lactation disorders cohort to date (1,382 patients and over 60,000 female controls), combining four major biobanks: Vanderbilt University’s BioVU11,12, Mount Sinai Hospital’s BioMe Biobank13,14, All of Us and UK Biobank15,16. We propose a rigorous pipeline combining various state-of-the-art with cutting-edge approaches developed by us and others to: (1) obtain a high-quality WES lactation disorders cohort by variant- and sample-level quality control (QC)17,18, annotations19, and impact predictions20-22; (2) perform computational case-control analyses for high impact variants23,24; (3) prioritize variants and genes by biological relatedness approaches25-27 and use a novel quad-culture organotypic mammary gland model to characterize the molecular pathology of high impact variants; and (4) perform phenome-wide association studies (PheWAS)28 and polygenic risk score (PRS) analyses29. We expect that our findings of human lactation disorders genetics will be vital for understanding the physiology and pathophysiology of human milk systems, directly informing maternal, perinatal, neonatal health decisions, and ultimately guiding precision medicine approaches to improve women’s health.

NHLBI - National Heart Lung and Blood Institute

Project summary/Abstract Epigenetic regulation is crucial for directing the intricate processes of heart development, and the disruption of these precise mechanisms underlies various congenital heart defects. Epigenetic mechanisms, such as histone modifications, play key roles in coordinating gene expression programs that guide early lineage specification and differentiation. Lysine-specific histone demethylase 1 (LSD1) is a critical epigenetic regulator that removes mono- and di-methyl groups from histone H3 lysine 4 (H3K4me1/2), thereby influencing chromatin accessibility and transcriptional activity. Beyond its enzymatic function, LSD1 also acts as a scaffold that coordinates transcription factors and chromatin remodelers. However, how these distinct functions of LSD1 contribute to cardiac lineage specification remains poorly understood. Studies have shown that LSD1 is essential for embryonic survival, and recent mouse models have revealed specific developmental cardiac defects in the absence of LSD1. For example, LSD1 hypomorphic mice with impaired protein-protein interactions exhibit ventricular septal defects and perinatal lethality. Additionally, cardiomyocyte-specific LSD1 knockout embryos display reduced heart size, dilation, and embryonic lethality, indicating that LSD1 is necessary at multiple developmental stages in specific tissues. Our lab has further shown that LSD1 knockout embryonic stem cells (ESCs) fail to generate mesoderm and endoderm, instead favoring neuroectodermal fates. Importantly, while the loss of LSD1’s catalytic activity impairs cardiac differentiation, complete loss of LSD1 fully blocks it, emphasizing the significance of its non- catalytic functions in early cell fate decisions. In this proposal, I aim to unveil the precise role and molecular mechanism of LSD1 in regulating cardiac specification and heart development. I will use in vitro and in vivo models to dissect the role of LSD1 in cardiac development. State-of-the-art approaches such as CRISPR/Cas9 guided genome engineering, novel animal models, epigenomics, and single-cell RNA-seq will be used to address the central question. This project will clarify how LSD1 regulates early cell fate decisions in cardiac development, with long-term implications for understanding congenital heart defects and advancing epigenetic-targeted therapies.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Retrotransposons are interspersed genomic repeats that constitute almost half of the mammalian genome. Largely residing in the heterochromatin, retrotransposons are transiently induced during early development to regulate lineage differentiation, and kept silenced in adult terminally differentiated tissues. However, in human diseases such as cancer and aging, retrotransposons often exhibit aberrantly elevated activities, whose underlying molecular trigger and functional consequences are less understood. Murine skin represents an excellent model to study retrotransposon silencing mechanisms. As our largest organ, skin harbors highly abundant, well characterized, and genetically accessible adult stem cells. Hair follicle stem cells reside in an anatomically distinct niche known as the bulge, alternating between quiescence and activation in a synchronized fashion to fuel cyclic bouts of hair growth. Over repeated insults, hair follicle stem undergo functional exhaustion, the molecular driving events of which were often unclear. In the current proposal, I plan to examine chromatin regulators that couple adult stem cell activation with retrotransposon suppression during adult skin and hair follicle regenerations. Two central heterochromatin pathways are known to silence retrotransposons: tri-methylation on histone 3 lysine 9 (H3K9), catalyzed by histone lysine methyltransferases (KMTs), and DNA cytosine methylation, catalyzed by DNA methyltransferases (DNMTs). Moreover, lineage gene expression during stem cell differentiation depends on DNA demethylation, catalyzed by the DNA demethylase ten-eleven translocation (TET). While TETs are crucial for DNA methylome remodeling in early development, their regulations of retrotransposons in adult tissues remain underexplored. My preliminary analysis of genetic models in which the endogenous retroviruses (ERVs, a type of retrotransposons), are reactivated to drive skin stem cell exhaustion and hair loss, afforded me a unique tool to tackle these questions. Specifically, my prelim data indicated that a critical signal connecting TET to H3K9 KMT and DNMT function is the post-translational modification known as O-linked-β-N-acetylglucosamine (O-GlcNAc). I hypothesize that OGlcNAc catalyzed by the OGlcNAc transferase (OGT) is essential to suppress ERVs by interacting with H3K9 KMT and DNMT in the skin. I will examine OGT-deficient skin phenotypes and O-GlcNAc changes upon ERV reactivation, and dissect the mechanisms of OGlcNAc-orchestrated ERV suppressions. Study proposed here leverage my previous training in mouse genetics, development, epigenetics, and skin biology, and are designed to further train me with the state-of-art technologies such as CRISPR and classic methodologies in biochemistry and molecular biology. My training plan and my sponsor/co-sponsor support have been tailored to further foster my critical thinking, scientific communication, leadership and career development goals within MDACC and GSBS training environment. The proposed study, if successful, will provide important mechanistic insights into retrotransposon biology in adult skin, and mature me into an independent researcher.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY More than 39.9 million people are living with HIV worldwide, including 1.2 million women who become pregnant annually. Suppressive antiretroviral therapy (ART) to pregnant women with HIV (WHIV) has been highly successful in reducing the number of new pediatric infections. However, HIV/ART exposure in utero and infancy can lead to reduced early life growth predisposing children for lifelong metabolic disease risk, so understanding adverse effects of HIV/ART exposure on infants is critical to protect millions of children worldwide. Human milk (HM) is essential for early infant metabolic health, and breastfeeding is recommended globally for WHIV on ART. However, HM is a complex mixture that is highly dependent on the maternal environment and HM components may influence child health. HM is rich in extracellular vesicles (EVs), nano-sized packages that survive digestion to deliver their bioactive cargoes. EV miRNAs (small noncoding RNAs) and metabolites (small polar metabolites and lipids) are important bioactive molecules that hold promise as drivers of these effects. Our goal is to investigate the role of maternal HIV/ART exposure on the HM EV-metabolome and EV-miRNAs and their subsequent impacts on child growth and body composition. To address this, we propose to leverage the Africa-based Obesogenic oRigins of maternal and Child metabolic Health Involving Dolutegravir (ORCHID) study of pregnant WHIV receiving tenofovir + lamivudine + dolutegravir (TLD) and HIV-seronegative pregnant women and their children (analyzing a subset, N=500; 250/group). Using anthropometry at 1, 2, 3, 6, 12 and 24 months of age and gold standard air displacement plethysmography to assess body composition, we will construct trajectories of overall infant growth and adiposity. In HM samples collected at 1 and 3 months postpartum, we will evaluate EV-miRNA expression with next-generation sequencing and the HM EV-metabolome with ultrasensitive metabolomics and lipidomics to address the following aims: Aim 1. Assess the association of maternal HIV/ART exposure with the human milk EV-metabolome and EV-miRNA across lactation; Aim 2. Investigate the associations of the human milk EV-metabolome and EV-miRNA with child growth; and Exploratory Aim 3. Develop a predictive multi-omic fingerprint of milk EV cargoes that can be used to identify HIV-exposed uninfected children (CHEU) with elevated risk of reduced growth and adiposity. Using machine learning approaches that account for joint effects and interactions, we will characterize miRNA-metabolome profiles in combination with traditional risk factors that identify children with elevated metabolic risk due to HIV/ART exposure during breastfeeding. With more than 1 million WHIV becoming pregnant each year and increasing numbers of children being exposed to HIV/ART through breastfeeding, our work will provide critical knowledge on how HIV/ART exposure impacts breastmilk composition and maternal-child communication to affect child health, providing key insights on nutrition and future targets for intervention and prevention.

NCI - National Cancer Institute

SUMMARY ABSTRACT: Cancer stem cells (CSCs) are a small population of cancer cells that are typically quiescent, but capable of self- renewal and tumor initiation. Non-CSCs, which make up the majority of the cancer cell population, are cells that are constantly dividing. Since CSCs are non-dividing, they are resistant to standard chemotherapy and radiation therapy, which only target actively dividing cells. Persistence of CSCs after therapy can thus result in disease relapse. Importantly, our recent work showed that programs of stemness are activated in tumor cells as they disseminate from primary tumors. Therefore, understanding what influences the formation of disseminating CSCs may provide new potential targets for therapeutic interventions of metastasis. Metastasis is a multi-step process and, in each step, disseminating tumor cells (DTCs) encounter different physical constrictions (e.g., physical confinement, solid stress, matrix stiffness, interstitial fluid pressure, and shear stress) that may affect their behavior. Recent reports in the literature indicate that one pathway for induction of programs of stemness is through the YAP/TAZ mechanotransduction signaling pathway, indicating that physical forces may, in part, be responsible for the induction of stemness in DTCs. This project will investigate the role physical constriction plays in stem cell induction by modelling the different physical constrictions that DTCs experience as they disseminate from primary tumors. This project will draw upon engineering and biological sciences to combine a unique, validated, fluorescent biosensor for stemness with advanced microfabricated microfluidic in vitro assays, and state-of-the-art intravital imaging of the live murine lung. We propose to use this combination to study the influence of physical forces on the selection, induction, and/or sustainment of metastasizing cancer stem cells, and evaluate their retention, survival, and extravasation efficiency in the in vivo lung.

Iowa Arts Council

Supports arts education projects in Iowa schools and communities, funding artist residencies, professional development for educators, and programs that integrate arts learning across the K-12 curriculum.

Iowa Arts Council

The Iowa Arts Council provides operating support grants to Iowa arts organizations, funding programming, staff, and operations that deliver arts and cultural experiences across the state's communities.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The antisense gene asp maps in the HIV-1 genomic region overlapping env at the SU/TM boundary. Asp is found in pandemic strains of group M, but not in other primate lentiviruses including non-pandemic HIV-1 groups N, O, and P. We showed that asp is highly conserved despite constraining the evolution of env. We also reported that the asp gene is found at a higher frequency in people living with HIV-1 (PLWH) who progress to AIDS in <3 years (rapid progressors) compared to those who progress to AIDS in >12 years (long term non-progressors). The asp gene encodes the 189-aa hydrophobic protein, ASP. We reported that ASP shows high sequence iden- tity across HIV-1 isolates from all group-M subtypes. Work from our lab described the presence of ASP on the plasma membrane of infected cells, and on the envelope of infectious HIV-1 particles. Our unpublished studies demonstrate that the presence of ASP on the surface of HIV-1 particles facilitates viral entry. Several studies have shown the presence of cellular and humoral immune responses to ASP in PLWH, which proves its expression in vivo. A recent report reported that antibodies against ASP were specific for epitopes in the predicted ectodomain of ASP. Our preliminary studies confirmed the presence of antibodies against the ASP ectodomain in Elite Controllers (EC). Yet, none of the studies published so far endeavored to isolate ASP anti- bodies from PLWH and to test their functional activity as a way to investigate the role of ASP in HIV-1 infection. The overall aim of this application is to isolate monoclonal antibodies (mAbs) against the ectodomain of ASP from EC, Viremic Controllers, and PLWH both on and off ART. We will test their activity in in vitro and ex vivo assays. These studies will be performed in collaboration with Dr. Mohammad Sajadi (Institute of Human Virology, University of Maryland School of Medicine), who has established a cohort of >200 PLWH from whom he has already obtained paired serum and PBMC samples that are immediately available for the studies proposed here. Dr. Sajadi has developed a method for the identification, isolation, and cloning of mAbs that led to the discovery of best-in-class mAbs against HIV-1, SARS-CoV2, and CCHFV. Here, we propose the following specific aims: In Specific Aim 1, we will generate pools of overlapping peptides that span the ectodomain of ASP, and we will use these peptide pools to screen serum samples from PLWH in Dr. Sajadi’s cohort to identify those with strong- est binding to each of the five ASP peptide pools, and to determine their peptide sequence specificity. Next, we will use single-cell PCR and mass spectrometry to isolate and clone high affinity anti-ASP mAbs from the paired PBMC samples of the same donors. We will then validate the ASP specificity of these mAbs in ELISA and virion capture assays. In Specific Aim 2, we will test the activity of the ASP mAbs in mediating antibody dependent cellular toxicity (ADCC), reducing viral entry in single-round infection and viral replication in multiple rounds of infection, and detecting ASP on the cell surface, in the cytosol, and within nuclei.

Festa Italiana

The 32nd Annual Italian Festival will be held on September 28-29th from 10AM- 8PM at Seattle Center, 305 Harrison St. This community festival is designed to celebrate the arts and culture of Italy and those Americans of Italian descent. The celebration will features exhibits, music, dance, food and activities for the entire family.

NIAID - National Institute of Allergy and Infectious Diseases

People with HIV (PWH) on antiretroviral therapy (ART) experience persistent immune activation and inflammation despite effective viral suppression. Over time, this results in chronic inflammatory conditions across multiple organ systems, including neurocognitive decline and liver disease. The high risk for these conditions in PWH necessitates the identification of therapies to suppress inflammation that would be an adjunct to ART. One promising approach is through inhibition of the JAK-STAT signaling pathway. Small molecule JAK inhibitors (JAKi) have been highly successful in treating chronic inflammatory diseases and a second-generation orally available JAKi, baricitinib, is FDA approved for rheumatoid arthritis, alopecia areata, and systemic inflammation associated with COVID19. Recently, two Phase 2 clinical trials were initiated to evaluate the ability ofbaricitinib to control HIV replication and associated inflammation in PWH. like all clinical trials, these are limited in the types of samples that can be collected, resulting in a restriction to the mechanistic understanding of any viral or immune benefits that are observed. This proposal will bridge this gap by testing baricitinib in SN-infected macaques on ART (SIV +ARn, a system that is recognized as the gold standard for mechanistically evaluating HIV treatments. Our studies will test the hypothesis that JAK inhibition will reduce levels ofinflammatory biomarkers in tissues ofSN+ARTmacagues better than ART alone and that this benefit will be present even in a heightened inflammation model of/ow-dose lipopolysaccharide (LPS). We further hypothesize that reduced inflammation will result in lower SN levels and a smaller SN reservoir due to a reduction in activation and homeostatic proliferation of SN target cells. We will test the hypothesis in two specific aims, the first will assess peripheral tissues (blood and lymph nodes), while the second will assesses deep tissue sites within the macaques (CNS, lungs, liver and GI tract). Inflammatory mediators, immune cells and viral reservoirs will be assessed at each of these tissue sites. This proposal is timely as it investigates JAKi as potential anti-inflammatory and anti-viral therapy in the context of SIV +ART macaques, assessing key tissue sites that cannot be easily accessed during human clinical trials. In addition, baricitinib will be evaluated in the context of heightened inflammation associated with low-dose LPS exposure, with the potential to uncover strengths or weaknesses regarding JAK inhibition that might not be observed in a clinical trial. The long-term goal of the proposed studies is to obtain mechanistic insights into the effectiveness of JAK inhibition during SIV+ART. If proven efficacious, it is possible that baricitinib will be utilized as a therapy to suppress inflammation, reduce HIV replication, reduce HIV reservoir size, and increase life expectancy for PWH. We hope that the repurposing ofbaricitinib to address a persistent problem for PWH will represent a paradigm shift in the treatment of chronic HIV infection in the United States and globally.

Japantown Planning Group

The Japantown Planning Group (with fiscal sponsor Wing Luke Museum) requests funding for our Sakura Cherry Blossom Festival, in Seattle's Japantown, with weeklong activities April 7-12 culminating with main events on Saturday, April 13. Business owners and community members in Japantown have worked together over several years to activate Japantown businesses, streets, and parks and encourage more economic and pedestrian activity to help our recovery. Last year, we held the first Sakura Festival with an invitation to spend time in the neighborhood and enjoy music performances, art installations, food and business specials, walking tours, giveaways, a photo contest, and picnics in Kobe Terrace Park during cherry blossom time. Venues such as the Danny Woo and Chiyo?s Garden, Nihonmachi Alley, KOBO at Higo, Sairen, Panama Tea House, Wing Luke Museum, and more helped attract a diverse crowd in a successful event. We hope to build on that success as we welcome in Springtime together!

Jefferson

Jefferson Who Am I? is a theatrical performance based on the relationship between Thomas Jefferson our 5th president and his slave mistress Sally Hemings. The work will be presented on September 29th and 30th of 2018 at the Langston Hughes Center using several artistic disciplines including poetry, art, music and dance and performers of all ages. The project will stimulate healthy conversation on race and equity in American today, through facilitated discussions with the cast. All performances/events will be free and open to the public.

Central Area Chamber of Commerce

From 12pm - 6pm on Saturday June 15th and Sunday June 16th the Central Area Chamber of Commerce will host a celebration marking the emancipation of slavery. This year marks the 36th Juneteenth celebration at Pratt Park located at 1800 South Main Street and whose namesake, Edwin Pratt, was a trailblazer of the Civil Rights movement in Seattle. Juneteenth evokes the feeling of a family reunion, with event highlights including live music, spoken word, dance, art activities for kids, food, local small business vendors and community organizations. This year Juneteenth will also include a commemoration of the late DeCharlene Williams, the founder and long time leader of the Central Area Chamber of Commerce.

Kandelia

Kandelia's Culture Fair is an event to celebrate youth, families, diversity, and community across Seattle. Culture Fair will occur on June 3rd, 2023 from 9:30am - 1:30pm at Seattle World School (SWS). We are using SWS because it is an existing place of significance for our community and is central in the city for convenience. Culture Fair will celebrate newly arrived immigrant and refugee families. It will be a community event featuring food, music, dance, fashion, arts & crafts, sports, and people from diverse cultures. Attendees will be able to sample foods from different countries, participate in a friendly soccer game, and learn about different cultures. The event will also feature youth performances that include cultural dances, music performances, and fashion shows. Kandelia will invite immigrants and refugee families throughout Seattle. We will share the invite with our network of community partners, volunteers and the Central District neighborhood that surrounds SWS.

Kansas Creative Arts Industries Commission

The Kansas Creative Arts Industries Commission provides operating support grants to arts organizations across Kansas, funding programming, staffing, and capacity building that sustain the state's cultural infrastructure.

Kansas Creative Arts Industries Commission

Supports specific arts projects and programs across Kansas including festivals, exhibitions, performances, and community arts events that bring creative experiences to Kansas residents.

Kentucky Arts Council

Supports arts education programming in Kentucky schools and communities, funding artist residencies, arts integration professional development, and creative learning experiences for K-12 students.

Kentucky Arts Council

The Kentucky Arts Council provides operating support to Kentucky arts organizations for ongoing programming, operations, and capacity building that sustain arts and cultural experiences across the Commonwealth.

Kids and Paper

Starting in September of 2021, Kids and Paper plans to launch a new afterschool program to serve resettled children in grades K-5 with homework help, tutoring and healthy meals, along with programming that helps participants work on their social and emotional development through creative arts at the Magnuson Community Center located at 7110 62nd Ave NE Seattle, WA 98115. The anticipated project close out date is January 31, 2022.