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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.

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.

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.

Jewish Community Federation of San Francisco

Supports Jewish education, social services, arts, and community programs in the San Francisco Bay Area.

Jewish Community Foundation (multiple cities)

Local Jewish community foundations in major U.S. cities provide grants for education, social services, arts, and community programs.

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.

Kresge Foundation

Supports programs that expand opportunity for low-income people in American cities. Focus areas: arts, education, environment, health, and human services.

The Kresge Foundation

Invests in place-based initiatives that advance opportunity in Native communities, focusing on arts and culture, education, environment, and health.

KS Arts Council

General operating and project support for arts organizations and individual artists in KS. Funds visual arts, performing arts, literary arts, and arts education.

KY Arts Council

General operating and project support for arts organizations and individual artists in KY. Funds visual arts, performing arts, literary arts, and arts education.

La Crosse Community Foundation

La Crosse Community Foundation ($75M in assets) supports nonprofits in WI through grants focused on education, community development, health, arts. Awards range from $1,000 to $25,000.

Lancaster County Community Foundation

Lancaster County Community Foundation ($150M in assets) supports nonprofits in PA through grants focused on education, arts, community development, health. Awards range from $1,000 to $50,000.

Lauder Foundation

Funds arts, culture, education, and Jewish community programs globally.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary The AIDS Clinical Trials Group (ACTG) has been at the forefront of clinical research to advance HIV therapeutics and improve the health of people living with HIV/AIDS for 30 years. Rigorous scientific research conducted by the ACTG has laid the cornerstones for current HIV treatment guidelines. In this application for the competitive renewal of the ACTG we propose a transformative research agenda that draws on an international consortium of leading clinical and laboratory HIV investigators in collaboration with a world-class Statistics and Data Management Center to design and conduct innovative interventional clinical trials that will significantly reduce the global burden of disease due to HIV, TB and hepatitis B. The Leadership and Operations Center (LOC) provides scientific leadership and fiscal and organizational management of the ACTG. The ACTG Executive Committee (AEC) will serve as the overarching governing body of the network. The AEC is guided by an Executive Management Committee that includes the Network Chairs, Chief Quality Officer and the Chairs of the Laboratory and Statistical and Data Management Centers. Transformative Science Groups will oversee the development and execution of the ACTG research agenda, which will be coordinated and prioritized by the Scientific Agenda Steering Committee (SASC). Protocol development, implementation, training and network evaluation will be facilitated by the Network Clinical Core at Social & Scientific Systems, Inc. The LOC financial management group (Admin Core) at the University of California, Los Angeles will oversee resource management and protocol fund distribution at the direction of the AEC. The LOC will assure the engagement of Community in all aspects of the ACTG, and will coordinate communication between all three components of the network. Specific aims of this proposal include: 1) Identify interventions to reduce HIV reservoirs and control HIV replication in the absence of ART; 2) Test novel and durable interventions targeting HIV infection; 3) Improve the treatment and prevention of drug sensitive and drug resistant tuberculosis; 4) Prevent or improve the treatment of HIV-related non-infectious co-morbidities and evaluate strategies to cure hepatitis B virus infection in people with and without HIV.

U.S. National Science Foundation

NSF s goal for high performance computing (HPC) in the period 2006-2011 is to enable petascale science and engineering through the deployment and support of a world-class HPC environment comprising the most capable combination of HPC assets available to the academic community. The petascale HPC environment will enable investigations of computationally challenging problems that require computing systems capable of delivering sustained performance approaching 1015 floating point operations per second (petaflops) on real applications, that consume large amounts of memory, and/or that work with very large data sets. Among other things, researchers will be able to perform simulations that are intrinsically multi-scale or that involve the simultaneous interaction of multiple processes. HPC Resource Providers - those organizations willing to acquire, deploy and operate HPC systems in service to the broad science and engineering research and education community - play a key role in the provision and support of a national HPC environment. With this solicitation, NSF requests proposals from organizations, or groups of organizations, willing to serve as a petascale HPC Resource Provider, and who propose to acquire and deploy a new, state-of-the-art, petascale HPC system. A competitive, petascale HPC system will: *Enable researchers to work on a range of computationally-challenging science and engineering applications at the frontiers of research; *Incorporate reliable, robust system software essential to optimal sustained performance; *Provide a high degree of stability and usability; and, *Function as a community-driven resource that actively engages the research and education communities in petascale science and engineering. A robust and effective HPC acquisition process, driven by the requirements of the science and engineering research and education community, is one of the key elements of NSF s HPC strategy. Accordingly, the desired capabilities of the system to be acquired are defined in terms of performance on model problems.

Lee Foundation

One of Singapore's largest philanthropic foundations supporting education, welfare, arts, and healthcare.

Friends of Art on Pier 86

Friends of Art on Pier 86 (FAP86) will project illuminated art onto the side of a building at Pier 86 in cooperation with the Port of Seattle. A pilot image or series of images will be projected for three months during the first half of 2018, and different art will be projected for a similar period at the end of 2018. They will do a call for artists, lead community workshops for input into art design, host opening events, and conduct community feedback surveys.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract Interorgan communication between the brain and peripheral tissues maintains a range of adaptive responses that can degrade with aging. Using mouse models, we found a powerful neural circuit that simultaneously motivates spontaneous activity and overrides spinal reflexes that control bladder and colonic function. Our preliminary findings show a strong direct neural circuit between estrogen-responsive neurons in the hypothalamus and the major micturition center in the hindbrain that controls urination, the Pontine Micturition Center (PMC) or Barrington’s nucleus (BAR). When activated, this VMHvl-BAR monosynaptic circuit blocks all voiding, even when animals have been pre-loaded with saline; when inhibited, urine release increases. Similarly, when a glass bead is inserted into the colon, excretion of this pellet takes up to fifteen times longer (20 minutes versus 5 hours) if chemogenetics is used to activate this neurocircuit. In vivo cystometry results confirm the potency of this hypothalamic-hindbrain circuit in modulating urine and fecal release. Here, we will define how neurons in BAR override normal spinal reflexes in the pelvic region. We outline three independent aims to: 1) identify the molecular nature of the inhibitory neurons in BAR responsible for this change in urinary and colon function and map projections from BAR to the spinal cord controlling the bladder or colon, 2) determine the sufficiency of VMHvl-BAR circuity components in urine release, and finally, 3) determine the initiating signals in the hypothalamus that control this voiding and defecation neurocircuit. This last aim will bring us closer to translating our preclinical research to human health. Our research program adds to emerging work on brain-body physiology to advance strategies for improving health and blends the team’s expertise in neuroendocrinology and neurocircuits. We are using state-of-the-art methods to pursue hypothesis-driven questions to decode a robust neuroendocrine circuit that controls two essential processes—urination and defecation. Both functions degrade with aging, especially in older women. Eventually, we wish to translate these preclinical studies to mitigate the loss of pelvic control in the older adult US population.