Grants

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Urinary tract infections (UTIs) affect approximately 150 million people per year worldwide. An estimated 50% of women report having had a UTI at some point in their lifetime. Antibiotic use, while the mainstay of UTI treatment, has contributed to the rise in antimicrobial resistance. Uropathogenic E. coli (UPEC) is implicated in about 75% of uncomplicated UTI cases, which has led to interest in understanding the mechanisms utilized by UPEC cause UTI. Previous work has shown that UPEC colonizes both the bladder and gastrointestinal (GI) tract, where UPEC is thought to establish a long-term reservoir and seeds the urinary tract. Thus, targeting UPEC in the GI tract could contribute considerably to UTI prevention by reducing UPEC shedding in the feces and subsequent colonization of the urinary tract. Previous work from our lab has shown that the susceptibility of UPEC to the host mucosal immune response in the GI tract depends on the localization of UPEC within the gut, which in turn is determined by the degree of microbial competition from other members of the gut microbiota. This competition can drive UPEC strains to occupy two distinct gut compartments depending on when they were introduced. When UPEC is introduced first in the gut, it inhabits the luminal and mucosal compartment, while a second strain, introduced after the first strain, prefers the mucosal compartment. Interested in the fitness factors and metabolic requirements that enable this differential localization, we created a barcoded transposon library in UPEC strain UTI89. Transposon libraries are an established tool for conducting genome-wide screens in bacteria. Furthermore, barcoding the library simplifies sequencing preparation, allowing users to test more experimental conditions. We tested our UTI89 pooled barcoded transposon library by growing it in different growth medias, which would allow us to both validate the library and reveal nutritional dependencies of UPEC in different environments. Aim 1 focuses on identifying UPEC fitness factors in vitro under conditions that mimic the gut environment. First, we will conduct an in vitro UTI89 pooled library screen in five different conditions. After validating the pooled library and identifying genes of interest in the mucin media condition, we will conduct another in vitro pooled library screen using the control, mucin-containing and glucose-containing media under anaerobic conditions, which we use to model the physiological gut environment. We have also assembled an arrayed version of this library which we will use to test gene candidates identified in both screens. Aim 2 will use gnotobiotic mice to perform an in vivo pooled library screen to identify fitness factors important in UPEC gut colonization when UPEC is introduced as a primary colonizer to a naïve gut and as a secondary invader in the presence of an existing gut microbiome. We will also test whether a low-fiber diet changes the landscape of UPEC gut colonization and repeat the above in vivo screen with mice on a low-fiber diet as an additional arm. Identifying UPEC fitness determinants will elucidate UPEC biogeographical niche occupancy and inform design of antibiotic-sparing interventions for UTI.

NHLBI - National Heart Lung and Blood Institute

Smokers are at increased risk for viral-induced respiratory failure and hospitalization. We have shown that cigarette smoking (CS) induces systemic inflammation characterized by increased interleukin 17A (IL-17A) expression in CD4 T helper (Th)17 cells in mice and humans. CS promotes Th17 cell differentiation in the lungs while reducing several key transcription factors critical in protecting against viral infection. Mice exposed to chronic CS and infected with influenza A virus (IAV) have increased IL-17A in the lungs, reduced flu-specific B cells, and increased mortality compared to controls. Consistently, in a prospective study, we have found that active smokers vaccinated against seasonal IAV have reduced flu-specific neutralizing antibody titers two months post-vaccination. Together, these findings indicate a strong link between smoking and reduced flu- specific memory B cell (Bmem) development. CD4 T follicular helper (Tfh) cells and dendritic cells (DCs) play a key role in mediating the selection and survival of B cells that differentiate into plasma cells, however, how CS changes their development or function remains unknown. Therefore, significant knowledge gaps include whether i) Tfh cells and DC numbers and/or function are perturbed in smokers with increased levels of IL-17A, and ii) B cell-Th17-axis impairs flu-specific antibody production and virus-specific Bmem development. Our central hypothesis states that CS increases IL-17A in the lungs which impairs the differentiation and/or function of Tfh subsets and DCs, decreasing protective immunity against IAV. We have assembled an outstanding team of physicians, immunologists, and bioinformatics to test our hypothesis with Specific Aims: Aim 1) Determine the mechanism of CS-induced loss of long-term protective flu-specific B cell immunity. Rationale: compared to controls, mice exposed to CS and IAV have increased Th17 cells in the lungs, reduced flu-specific antibodies, and blunted HA-specific B cell responses. This aim will test the hypothesis that active CS induces IL-17A in the lung that alters systemic and transcriptional factors required to produce protective Bmems. Aim 2) Determine flu-specific memory B cell function and transcriptomic changes in the lungs of smokers. Rationale: compared to controls, active smokers have increased Th17 cells and reduced flu-specific Bmems in the lungs. This Aim will test the hypothesis that ineffective expansion of flu-specific Tfh cell pool in the lung correlates with poor Bmem survival and lack of high-affinity antibodies against IAV in humans. Aim 3) Determine the mechanism involved in systemic immune responses to flu antigens in smokers. Rationale: compared to controls, active smokers show reduced neutralizing antibody titers following flu vaccination. This Aim will test the hypothesis that CS induces systemic changes to the immune cell transcriptome required to develop protective Bmems in response to seasonal flu vaccination. Impact: Unraveling the mechanisms for failure to develop protective antibodies against flu in smokers provides critical evidence for designing human clinical trials and testing new treatments for this at-risk population.

Marion County

Detroit Lake Marina Sediment Assessment

Deuce 98 Block Watch

On August 4, 2015 from 4:00pm to 9:00pm, the Deuce 98 Community Block Watch Neighbors will hold a block party to celebrate Safety/Awareness and Cultural Diversity by sharing food, music, voices and games representing the neighborhood. There will be a Safety and Awareness potluck, live entertainment, art activities, and children's games. It will be free & open to the public.

Dept of the Army -- Materiel Command

DEVCOM ANALYSIS CENTER BROAD AGENCY ANNOUNCEMENT FOR APPLIED RESEARCH

Dept of the Army -- Materiel Command

DEVCOM ARMY RESEARCH LABORATORY BROAD AGENCY ANNOUNCEMENT FOR FOUNDATIONAL RESEARCH

DECD

Develop a Freight Street Redevelopment Strategy.

NCI - National Cancer Institute

Project Summary Spot-scanning Proton Arc (SPArc) therapy is an emerging treatment modality that has shown potential clinical benefits for a wide range of disease sites. Unlike the conventional step-and-shoot multi-field Intensity Modulated Proton Therapy (IMPT), SPArc therapy utilizes arc trajectories for planning and treatment. The extra degree of freedom offers superior dose conformity which is particularly crucial for treating head and neck squamous cell carcinoma (HNSCC) patients, where organs-at-risk (OARs) are often adjacent to the target volume. Therefore, sharp dose fall-off using SPArc therapy is able to reduce radiation-induced toxicity. In 2018, the concept of SPArc therapy was successfully demonstrated in a clinical Proton Therapy System (PTS) equipped with a synchrocyclotron accelerator and partial gantry. This breakthrough drew significant interest from the radiation oncology community. However, the clinical implementation of SPArc therapy faces several challenges. (1) Slow optimization speed: Because of the mathematical complexity and optimization burden associated with numerous spot and energy layers, it takes hours to optimize a treatment plan; (2) Prolonged treatment delivery time: Various PTS have different machine-specific delivery sequences (MSDS) such as synchrotron, cyclotron, and synchrocyclotron accelerators. It makes it almost impossible to generate a universal delivery-efficient plan across all the different PTS. Some treatment times could be doubled because the key plan parameter does not fit the specific type of PTS even with an identical plan that worked for another PTS; (3) Dose errors in the dynamic treatment delivery: The accuracy of proton beam therapy is heavily reliant upon beam angle and its associated water-equivalent-path because of the sharp distal fall-off. Delivering the dose continuously during gantry rotation could cause unnecessary dose error between the "true" dynamic delivery and the static nominal plan, leading to the degradation in local tumor control probability by about 5% for the HNSCC patient population. To overcome these impediments and enable the clinical implementation of SPArc therapy on a global scale, this project will develop a novel multi-approach dynamic SPArc optimization framework that ensures fast optimization, efficient treatment delivery, and accurate dosimetry for various types of PTS. The project includes three specific aims: (Aim 1) Systematically investigate machine-specific delivery sequences of various PTS and establish SPArc simulators; (Aim 2) Develop a fast sparsity optimization framework; and (Aim 3) Introduce “true” dynamic sequencing SPArc optimization framework and assess the improvement in the treatment delivery accuracy. The results of this study will provide the first-of-its-kind SPArc delivery simulator and an open-source SPArc sparsity optimization framework, benefiting global investigators and researchers and facilitating prospective clinical trials.

OPM

Develop a Regional Bike and Pedestrian Plan for the Southeastern Connecticut Planning Region.

DOT

Develop a Regional Complete Streets Policy and Action Plan.

DEEP

Develop a study comparing alternative routes for the HouBike Trail between Kent and the Cornwall Bridge.

DEEP

Develop a study to establish an official route for a 7-mile gap in the Naugatuck River Greenway between the Thomaston Dam and Bogue Road in Torrington.

DPH

Develop a study to identify potential options for water and wastewater infrastructure within the West Cornwall village center.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY: Yu Liu, PhD (Principal Investigator; PI) LncRNAs are >200nt RNA molecules that do not translate into protein products. The number of lncRNAs is far greater than their protein-coding counterparts, but the functions and underlying mechanisms of lncRNAs are less understood. A few lncRNAs modulate the expression of their target genes through forming an RNA-DNA triple helix at gene regulatory regions such as enhancers and promoters; this new layer of gene regulation is particularly important for developmental gene expression programs. However, knowledge about this new regulatory mechanism is scarce. The research community mainly relies on candidate lncRNA-based methods, not unbiased whole-genome approaches. The major technological challenge is that we cannot reliably capture whole-genome RNA-DNA triplexes in vivo. We propose to capture RNA-DNA triplex by using the differential affinity of Thiazole Orange (TO) to complex helical structures vs. canonical structures. TO is a classic fluorochrome for double-stranded DNA (dsDNA), but its affinity to triplex and quadruplex structures of DNA is substantially higher. Because RNA-DNA triplex is structurally comparable to, but more stable than DNA triplex, we predict that we can use TO to identify genomic RNA-DNA triplexes. The core of this new technology, TO-Triplex-Seq, comprises Biotin-conjugated-TO labelling and subsequent Avidin-pulldown, followed by DNA purification and sequencing. We will distinguish RNA-DNA triplex from other complex helical structures using special RNAse treatments in parallel chromatin samples. The unique strength of this new technology is that we will specifically capture RNA-DNA triplexes, not other complexes in which RNA and DNA form a duplex (R-loop) or indirectly interact through other binding partners. We will prove the concept and validate this new technology with two specific aims. SA1 will determine the affinity between TO and synthetic RNA-DNA triplexes and test the framework of pulling-out RNA-DNA triplexes from a pool containing RNA-DNA triplexes, DNA-only triplexes and dsDNAs. SA2 will establish and validate the new technology using a multi-scale approach. We will (1) characterize the sequence features of the RNA-DNA triplex sites; (2) study how triplex formation changes during active and suppressed rRNA biogenesis which is regulated by a pRNA-rDNA triplex; (3) study whether distinct sets of lncRNAs contribute to triplex formation in undifferentiated and differentiated hESCs; (4) further annotate the RNA-DNA triplex datasets to publicly available chromatin state datasets. At the conclusion of this project, we expect to publish a detailed protocol which others can easily adopt and further build upon. Ultimately, we plan to develop a TO-labeling- based multiomics toolset that comprehensively describes the RNA, DNA, and even protein components (if present) of RNA-DNA triplexes and hence contributing to the understanding of transacting lncRNAs.

DECD

Develop an agricultural business incubator, community farm

OPM

Develop detailed station area plans for the Downtown, East Main Street and East Street CTfastrak stations.

National Park Service

United States Departement of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This funding opportunity is to provide public notice of NPS's intention to fund the following project activities without full and open competition. Task Agreement #P15AC01667 under Cooperative Agreement P13AC00676 with the University of California, Berkeley, a partner under the California Cooperative Ecosystem Studies Unit, for the project titled, "Develop Grazing Guidelines for the Ash Mountain Pasture in Sequoia and Kings Canyon National Parks."

National Park Service

United States Department of the Interior, National Park Service Notice of Intent to Award. This Funding Announcement is not a request for applications. This announcement is to provide public notice of the National Park Service's intention to enter into a cooperative agreement with the Siskiyou Field Institute for a project titled, "Develop Oregon Caves Youth Programming." The commitment of funds in furtherance of the cooperative agreement will be authorized by the execution of individual task agreements identifying the project activities, the amount of financial assistance and any other special terms or conditions applicable to the project activities.

Healthy Othello Safer Through Environmental Design (HOSTED)

Healthy Othello Safer Through Environmental Design (HOSTED) would like to make improvements in the right of way located at 3900 South Othello Street to improve everyone's safety. The project will include installing planters with colorful plants selected and maintained by the community to separate the vehicle space from pedestrian space, painting the pavement/obstructions to help pedestrians of all abilities move through safely. The project is expected to be done by September of 2020.

NCATS - National Center for Advancing Translational Sciences

The contractor shall develop OR adapt/use previously developed (if available): anti-drug antibody (ADA) and neutralizing antibody (NAb) assays as well as T-cell immunogenicity assays to support NACTS clinical trials including the MMA-101 gene therapy candidate and implement the assays for testing of clinical samples for the FIH clinical trial of MMA-101. The contractor shall qualify OR use already available qualified anti-AAV8, anti-MMUT, AAV8 NAb assays, and anti-AAV8 and anti-MMUT T-cell assays. The NAb assay must be performed in a CLIA certified laboratory because its results will be used to determine eligibility of MMA patients for the FIH clinical trial of MMA-101. Clinical trial endpoints also include anti-AAV8 and anti-MMUT antibody levels and T-cell responses to AAV8 capsid proteins and MMUT (Elispot or Fluorospot). Thus, all these assays will need to be developed, qualified, and performed on clinical trial samples for the study. Not more than 50 MMA patients will be screened for eligibility (NAb assay). The anti-AAV8 and anti-MMUT tests will be performed for up to 6 research subjects at baseline and Study Days 5, 14, 42, 56, 84, 168, 364. The NAb assay will be performed at baseline, Study Days 5, 14, 42, 56, 84, 168, 364, and Years 2, 3, 4 and 5 post MMA-101 administration. Reporting of data must be CLIA compliant for the NAb test performed for study eligibility, and cGCP-compliant, per study protocol, for the NAB and anti-AAV8 and anti-MMUT assays performed throughout the execution of the FIH study. The T-cell assays will be performed for up to 6 research subjects at Study Days 56, 84, 168, ad 364 after MMA-101 infusion. Sample processing, shipping, results transmission, and all related activities must follow the qualified methods, clinical protocol, Laboratory Manual, and related documentation. Contractor shall develop controls, standards and critical reagents, and SOPs to support clinical trial sample testing for NCATS trials or studies of interest to NCATS. Contractor shall provide a written results summary with data and a complete study report (IND format) after all subtasks are completed, including: a) the plan for assay development OR adaptation (if assay already available) and implementation of NAb, anti-AAV8, anti-MMUT antibody assays, and T-cell assays; b) a detailed description of the assays; c) the plan for testing of the clinical trial samples, including CLIA-compliant NAb assay; and d) all test results from the evaluation of the clinical samples.

NHGRI - National Human Genome Research Institute

Project Summary Understanding how genetic variation impacts gene regulation is essential for linking noncoding variants to disease risk and transcriptional dysregulation. While cis-regulatory elements (cCREs), such as enhancers and promoters, play a central role in transcriptional control, their activity is highly cell type-specific, and most allele specific regulatory studies have been conducted at the bulk tissue level, limiting resolution. Additionally, previous studies have largely focused on gene-level expression changes, overlooking how regulatory variation affects alternative isoform usage, which has important implications for human disease. This project will integrate large-scale regulatory annotations with allele-specific analyses at the single-cell level to improve our understanding of how noncoding variation shapes transcriptional regulation. Aim 1 will establish a cCRE workspace and analysis framework in AnVIL, integrating the ENCODE Registry of cCREs into a cloud-based platform to support scalable and reproducible analyses of transcriptional regulation. We will develop modular workflows for cCRE annotation, cell type-specific scoring, and transcription factor footprinting, along with the STELLA suite, a collection of computational tools for regulatory genomics. Aim 2 will investigate how allele-specific cCRE activity influences isoform usage in individual cell types using data from the Genomic Answers for Kids (GA4K) project. We will construct personalized diploid genomes to identify allele-specific cCREs (from single-cell ATAC-seq) and allele-specific isoform usage (from bulk long-read RNA-seq). Using a Dirichlet-Multinomial deconvolution model, we will infer cell type-specific isoform expression, validated with ENCODE Split-seq data. We will then use a hierarchical regression model to test whether allele-specific cCREs predict allele-specific isoform usage, incorporating cell type assignment probabilities. Finally, we will apply ChromBPNet deep learning models to assess the functional impact of noncoding variants on transcription factor binding. By integrating these analyses into AnVIL, this project will create generalizable computational frameworks for regulatory genomics, enhancing the usability of NHGRI-funded resources. The methods and resources developed will enable broad applications across diverse datasets and disease studies, ultimately improving our ability to interpret noncoding variation in gene regulation and human disease.

NHGRI - National Human Genome Research Institute

This project’s main objective is to put forth an undergraduate program titled “Developing a Certificate in Computational Genomics and Biomedical Data Science” (CGBDS) at the Texas Undergraduate Medical Academy (UMA) on the campus of Prairie View A&M University, a member institution of the Texas A&M University System. It hereby responds to the RFA-HG-23-002 “Broadening Opportunities for Computational Genomics and Data Science Education'' by providing prospective students with basic knowledge and skills to pursue a rewarding career in the health care practice and/ or research. The proposed curriculum underpinning this certificate is structured into four interconnected courses: Computational Genomics (CoGen), Biomedical Data Science (BiDaS), Biostatistics/ Biomathematics (StaMa), and Bioinformatics (Binfo). CoGen and BiDaS syllabi will be correlated to deal simultaneously with genomic and biomedical aspects of the same human diseases. While StaMa and Bionfo will help students learn and exercise handling and processing data from the aforementioned human diseases. Moreover, these courses will comprise practical sessions that will be organized in the fully equipped UMA laboratories for bioinformatics, genomics, and molecular and cellular b iology experiments. During this program, we will train the students on how to use NIH-supported cloud computing resources, particularly NHGRI AnVIL (Genomic Data Science Analysis, Visualization, and Informatics Lab-space). Genomic and biomedical data for training exercises will be downloaded from publicly accessible NIHcurated repositories including but not limited to: NIH National Cancer Institute Genomic Data Commons Data Portal, eMERGE (Electronic and MEdical Records and Genomics Project), PAGE (Population Architecture Using Genomics and Epidemiology), and Convergent Neuro Consortium.Thus, these courses aim to help the students understand what genomic and medical big data are, how they have been generated, how to interpret them, and how to use them for predicting further implications. To this end, these courses will be delivered by four very experienced UMA faculty. These faculty members are cognoscible in their respective fields. These courses will be integrated within the curriculum of the school of public health and eventually as the foundation for a degree in Health bioinformatics.

NINR - National Institute of Nursing Research

The purpose of this proposed study is twofold: First, we propose to develop a deeper understanding of the experiences of severe maternal morbidity among survivors, their families, and their communities, and explore the boundaries of what is considered severe maternal morbidity (SMM) versus other severe complications of pregnancy. Second, we propose to develop community-driven intervention strategies to improve maternal, child, and reproductive health outcomes. All work will be guided by and developed in collaboration with an established community advisory board focused on SMM and maternal health. In Aim 1 we will use a lifecourse lens to conduct in-depth interviews and surveys with survivors of SMM. For Aim 2 we will recruit partners, family members, and support persons of SMM survivors to participate in interviews and surveys to understand their unique experiences which have often been overlooked. In these aims we will explore and describe the experiences, challenges, assets, and strengths of women affected by severe maternal morbidity and other serious complications of pregnancy; and characterize the experiences of partners, family members, and support persons. We will identify long-term consequences of SMM, evaluate social drivers of health of SMM survivors, and better define the boundaries of what is considered SMM from the patient and community perspective vs. a medical or epidemiologic perspective. We will identify causes, contributing factors, and consequences of SMM and other harms experienced by survivors and their families or support persons; survivor, family, and community strengths; health systems structures; and policy implications. In aim 3 we will be guided by causal mapping from Aims 1&2 and community-based prioritization of these factors in selecting priorities for intervention. We will then prototype, in collaboration with SMM survivors and family members, community partners, clinicians, community birth workers, administrators, and policy makers, an intervention strategy or strategies to address their priority concerns in maternal, child, and reproductive health. We will use the 6 Steps to Quality Intervention Design model to enhance prototype readiness for feasibility and acceptability testing as well as future large-scale testing, implementation, and dissemination. This study integrates the NINR strategic plan lenses prevention and health promotion, and systems and models of care to develop community-driven interventions to prevent SMM; mitigate the impact of SMM on survivors and their communities; and promote positive maternal, child, and reproductive health outcomes.

NIA - National Institute on Aging

This proposal responds to an acute challenge currently underserved by technology; the need to leverage novel approaches to develop cost-effective and responsive digital, mobile, website, and artificial intelligence (AI) tools to encourage participation in Alzheimer disease and related dementias (ADRD) clinical trials. With ADRD cases expected to double by 2060, efforts to ensure adequate participation in ADRD clinical trials is paramount to ensuring successful biomedical advances and drug development. Despite ongoing efforts to improve ADRD outcomes and clinical trial participation, no digital solution exists which has been purposefully designed and co-developed in partnership with patients at higher-risk of ADRD or with informal caregivers of ADRD patients critical in addressing challenges associated with trial participation. In response, this project utilizes approaches in digital tool development, AI, qualitative interviews and small group discussions, and use of co-design workshops to develop a multi-modal digital tool incorporating mobile, website, and AI chatbot features that will improve the education, recruitment, and enrollment of older adults in ADRD clinical trials. This will be accomplished by developing a trial matching algorithm specific to ADRD trials, conducting interviews with older adults and ADRD patient caregivers to identify specific challenges to participation, and facilitating a series of co-design sessions to develop digital tools designed to encourage trial participation among all older adults responsive to these challenges. It has the following aims: Aim 1: Develop a dedicated and up-to-date clinical trial matching algorithm for ADRD trials that will be further iterated on, refined, and incorporated into the MVP digital tool (M1: Create an ADRD trial matching algorithm within 1-2 months of project start); Aim 2: Conduct in-depth interviews and small group discussions with older adults and ADRD caregivers to identify factors related to clinical trial participation and use of digital, mobile, website, and AI technology, which will be used to inform digital tool features and the matching algorithm (M2: Complete in-depth interviews with 30 older adults and 30 caregivers by months 3-4); Aim 3: Co-design an MVP digital tool incorporating mobile, website, and chatbot modalities with older adults and ADRD caregivers and conduct business hypothesis testing (M3: Complete co-design sessions, develop and demo two versions of the MVP to at least 3 potential customers/strategic partners by the end of month 6) This is a significant opportunity to address increasing rates of ADRD among the growing aging population with the use of different digital health technologies. This project will lead to the co-design and development of user-centric tools to improve clinical trial outreach and participation of all older adult populations while also enabling more precision-based recruitment strategies to advance treatment and biomedical innovation for ADRD.