Grants

Dawson College Foundation

Dawson College Foundation is an active grantmaking foundation based in Glendive, MT. Focus: general. Contact the foundation directly for current funding opportunities.

Day School Foundation

Day School Foundation is an active grantmaking foundation based in San Mateo, CA. Focus: education. Contact the foundation directly for current funding opportunities.

Brooklyn

Day Street Embankment Stabilization

United Indians of All Tribes Foundation

Daybreak Star houses Indigenous Art the Sacred Circle Gallery and also hosts large community events such as Seafair Indian Days Powwow and Indigenous Peoples' Day. Daybreak Star's restrooms are not ADA-compliant. This project will develop a design to turn a closet into a universal, accessible, single restroom on the upper level of the building and modifications for the lower level restrooms to comply with current accessibility codes. This project will be completed by February 2019.

City of Gainesville

DaySpring MB Church

City of Gainesville

Dayspring Missionary Baptist Church

Dayton Childrens Hospital Foundation

Dayton Childrens Hospital Foundation is an active grantmaking foundation based in Dayton, OH. Focus: health. Contact the foundation directly for current funding opportunities.

Thurmond Real Estate Holdings

Preservation

Agriculture, Food&Mrkts Agency

DBIC 19M

Agriculture, Food&Mrkts Agency

DBIC 25

Yates County Genealogical and Historical Society

DBQ Collaborative Curriculum Project

Yates County Genealogical and Historical Society

DBQ Collaborative Curriculum Project **RECONSIDERATION**

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Proximal tubule injury is an important mediator of chronic kidney disease (CKD) and single-cell sequencing has shown that human and animal models of CKD result in an increased proportion of proximal tubule cells with a pro-inflammatory phenotype. Subsequent rounds of proximal tubule injury and repair can result in the accumulation of DNA damage, leading to persistent activation of the DNA damage response pathway and injury of neighboring cells via secretion of cytokines. We have developed novel methods to estimate DNA damage burden in proximal tubule cells by characterizing somatic copy number alterations (CNA). Somatic CNA occur when a cell gains or loses a portion of its genome and cells with high proliferative rate, like the proximal tubule, may be particularly susceptible to somatic CNA. These alterations are more common than was previously thought and can be as large as an entire chromosome, which likely affects the ability of proximal tubule cells to repair themselves. We identified increased expression of DCLK1 in injured proximal tubule cells that was further increased in cells with somatic CNA and we hypothesize that targeting these cells may help to slow progression of CKD. DCLK1 is a microtubule-associated protein kinase that is important for cell division, DNA damage response, and epithelial-mesenchymal transition (EMT). DCLK1 may act as a pro- survival signal that helps injured proximal tubule cells to evade apoptosis while they attempt to repair DNA damage. However, a subset of injured proximal tubule cells may have DNA damage that is too severe to repair, resulting in persistent activation of the DNA damage response pathway. DCLK1 is of particular interest because increased DCLK1 expression correlates with fibrosis, it is conserved in animal models of kidney disease, and it has been associated with CKD in a genome-wide meta-analysis. Much of what is known about DCLK1 comes from the study of cancer, which has led to the development of DCLK1 inhibitors that selectively limit the kinase activity of DCLK1 to attenuate downstream inflammatory pathways. These advances present an opportunity to repurpose DCLK1 inhibitors for CKD, but relatively little is known about how DCLK1 regulates inflammation and the DNA damage response in injured proximal tubule cells. DCLK1 has at least two isoforms that play variable roles in cell survival and inflammatory signaling. We hypothesize that proximal tubule injury and DNA damage result in biased expression of the short isoform and activation of pro-inflammatory signaling. We propose to quantify the ratio of DCLK1 long and short isoforms in human kidney. We will selectively target DCLK1 signaling in an animal model of CKD and further validate our predicted signaling mechanisms in cell culture models of the proximal tubule.

Dorchester County

DCS Facilities Repair

Dorchester County

DCS Facilities Repair

NSF

This doctoral dissertation research improvement award supports research on how scientists structure and share genomic data, especially across disciplinary boundaries. The goal of this study is to identify the anticipated and unanticipated effects of genetic data practices to help scientists, decision-makers, and funders to better understand practices and structures of sharing genomic data. The findings of this research may contribute to data sharing practices, managing and controlling the downstream use of genetic data, as well as to improving data management and privacy. This study will trace the origins and circulation of specific data, data structures, and data-sharing practices in genomics, as well as the adaptation and consequences of those practices in social science genomics. The use of mixed methods will permit an understanding of the social and historical context of data sharing through the review of scientific and popular literature; semi-structured interviews; and participant observation. It will focus on online databases collecting genetic data, consortia for meta-analyzing these data, and cloud-based platforms for managing data analysis. The intellectual merit of the project will focus on the active role that data and data practices play in the negotiation of genomic objects, frameworks, and practices through data management. The study will contribute to the literature on studies of scientific field dynamics and critical studies of data centric science. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF

This research examines how visions of a global “information age” have changed ways of conceptualizing and experiencing human potential. The dissertation study uses three case studies to examine the interplay between embodiment and technoscience. This work addresses broader contemporary concerns about how information technologies have intimately changed the way people understand themselves and their connection with their surroundings. The results of this project are communicated through conference presentations, journal publications, and undergraduate teaching. Combining state archives with records from published books, journals, media reports, laboratory reports, and memoirs, the project examines how the information revolution also entailed a transformation of human bodily understanding. The study asks: 1. How did medico-scientific and technological practices generate new visions of human capability and potential, and how did these intersect with visions of technoscientific modernization? 2. How have theories such as information theory, systems science, and cybernetics become localized and how do they interact with vernacular medical knowledge to shape new understandings of the human body as an informational entity? To address these questions, the project combines theoretical frameworks from Science and Technology Studies with archival research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

FDA - Food and Drug Administration

Project Summary Liver disease can significantly affect the bioavailability of drugs due to altered hepatic metabolism and transporter activity. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the United States and affects nearly 30% of the global population. Significant alterations in drug metabolizing enzymes have been observed in MASLD patients with both increased and decreased activity being reported which affect the clearance of drugs potentially resulting in adverse drug reactions or apparent inefficacy. Current approaches used to estimate dosing in clinical trials that are based on healthy liver function are inadequate for drugs in development for patients with liver disease. Thus, there is an unmet need in understanding how to effectively translate safety and pharmacokinetic (PK) data from healthy volunteers to a patient population with liver disease. Our human liver acinus Microphysiological systems (LAMPS) platform has been optimized to maximally recapitulate liver structure and function to address the complexity of studying absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox), in both healthy and diseased liver states. One of the objectives of our Translational Center for microphysiological systems (TraCe) is to qualify the LAMPS platform as a drug development tool (DDT) to establish the hepatic clearance of drug candidates in patients with MASLD and assist in the determination of drug candidate dosing in clinical trials when patients with MASLD are included. Our letter of intent for this context of use was determined to be reviewable by the Innovative Science and Technology Approaches for New Drugs program. In this proposal we are addressing two gaps that need to be filled for advancing to the next step towards qualification: 1) expand the number and range of reference drugs to validate the DDT for determining changes in hepatic clearance and the need for dose adjustment in patients with hepatic impairment; and 2) establish the concordance between the LAMPS disease phenotypes and clinical stages of hepatic disease to better define which patient population will benefit from the predicted dose adjustments.

NIGMS - National Institute of General Medical Sciences

This proposal aims to design proteins from scratch that can undergo intramolecular allosteric regulation, a process crucial to central metabolism, genetic regulatory networks, and biological sensing. If we truly understand the molecular biomechanics behind allosteric regulation, then we should be able to design proteins that use remote binding of a ligand to control small molecule release. Recent work has demonstrated the possibility of changing remote protein conformation through fold switching or domain displacement. Researchers from my postdoctoral training lab have shown that designed proteins can bind small molecules with sub-nanomolar affinity, designed enzymes can use a remote binding event to suppresses reactivity, and designed membrane proteins acting as part of a protein complex can transmit information from one binding event to influence distant kinase activity. Building from these recent advances in protein design, as well as the wealth of experimental data on signal transduction in helical bundle proteins such as G-protein coupled receptors and histidine kinases, the proposed research aims to develop new helical bundle proteins where binding of a ligand at one site increases the population of protein in a strained conformation, causing small molecule release at a second site. The capacity to design targeted proteins capable of small molecule delivery in response to changes in ligand concentration would give rise to powerful new capacities for biotechnology, and this proposal aims to explore release of two drugs for which de novo protein binders have been recently designed. In Aim 1, I will design a protein that releases the anti-cancer drug rucaparib upon binding of the pro-tumor metabolite itaconate. In Aim 2, I will design a protein that releases the anti-cancer drug apixaban following itaconate binding. Binding sites for the allosteric ligand and releasable molecule will be incorporated onto protein scaffolds built from stable helical bundles in combination with loops and kinks generated from diffusion-based probabilistic models. The resulting proteins will be expressed and purified, their binding will be assayed using fluorescence spectroscopy, and their structures will be determined using X-ray crystallography and NMR spectroscopy. Once successful allosterically regulated proteins are designed, new ligand binding sites will be positioned increasingly distal to the active site to explore progressively more remote strain transduction. Demonstrating intramolecular allosteric regulation within a single protein monomer will extend our understanding of a longstanding problem in protein biophysics. The proposed research project will advance my training goals as I integrate computational protein design, molecular biology and biochemistry techniques for cloning, protein expression and purification, and biophysical characterization. Combining my existing experience in physical chemistry with the skills developed during the proposed research will prepare me for an independent research career using proteins and synthetic macromolecules to understand and intervene in strained biological macromolecules.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Understanding the relationships between three-dimensional protein structure, metal reactivity, and catalytic function promises routes to new drugs and treatments, green chemical processes, and bespoke catalysts. However, the complexity of natural metalloenzymes makes the design of wholly new enzymes one of the greatest challenges in chemical biology. Thus, the de novo design of functional metalloproteins, in which both the protein scaffold and metal-containing active site are designed “from scratch”, presents the most stringent test of our understanding of protein folding and protein-metal structure-function relationships. Using new machine-learning tools for protein design and structure prediction, this work will investigate metalloenzyme structure-function relationships though the de novo design of vanadium- and heme-dependent haloperoxidase enzymes. These enzymes oxidize halides (X–) to X+ using H2O2 to promote halogen incorporation into diverse organic substrates. Halogen atoms often greatly increase the bioactivity of organic compounds, making these reactions important both for human health (e.g., pharmaceuticals, hormones, antibiotics) and the environment (e.g., toxic and ozone-depleting aerosols such as bromoform). The designed proteins will be expressed and characterized using a diverse array of structural, biophysical, and spectroscopic methods. Haloperoxidase activity will be measured, and the effects of primary and secondary sphere mutations will be studied. Potential alternative reactions catalyzed by the enzymes will be assayed, and the binding and activities of similar metal-oxo species (e.g., MoO42–, WO42–) will be investigated. By designing haloperoxidases using only minimal starting motifs, this work will provide valuable insights into the requisite structural and chemical features enabling efficient haloperoxidation catalysis.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Protein-small molecule interactions regulate protein function, signal transduction, and enzymatic catalysis in biological systems. Advances in protein engineering have enabled modifications of natural protein-small molecule interactions for diverse applications, including developing protein tags for fluorescence imaging and engineering enzymes for biocatalysis. However, designing de novo proteins to bind small molecules and catalyze reactions remains a significant challenge, often requiring extensive screening and experimental optimization. In my recent work, I developed a nature-inspired strategy leveraging weak protein affinities for non-primary substrates to create functional proteins. Using this approach, I designed Fluorescent ABLE (FABLE), a fluorophore-binding protein, and Kemp eliminase ABLE (KABLE), an enzyme for Kemp elimination. The initial Kemp eliminase design achieved an activity of 6600 M⁻¹s⁻¹ in just five attempts, surpassing previous computational designs by over an order of magnitude. Saturation mutagenesis produced a quadruple mutant with an activity of 600,000 M⁻¹s⁻¹, setting a new benchmark for base-catalyzed Kemp eliminase and outperforming mechanistically similar natural enzymes. These successes highlight the frontier of de novo protein design for specific ligand interactions. A deeper understanding of protein-small molecule interactions in de novo proteins is crucial for advancing both fundamental understanding of these interactions in Nature and practical applications in protein engineering, particularly in the development of protein tags for fluorescence imaging and the design of enzymes for biocatalysis. In this proposal, In this proposal, I aim to test my hypothesis that protein dynamics, particularly the enrichment of productive conformations, contribute to the enhanced rate of KABLE1.4 using a multidisciplinary approach that includes molecular dynamics, X-ray crystallography, and NMR (Aim 1). For fluorescence imaging, I will transform the proof-of-concept de novo protein (FABLE) into a set of ready-to- use protein tags by designing proteins that bind modern rhodamine fluorophores while equipping them with a predefined set of optimal features that no existing tool offers (Aim 2). Lastly, I propose engineering de novo proteins with covalent ligand interactions, allowing stable binding and a universal protein tag for various synthetic molecules without requiring sequence redesign (Aim 3). Harnessing de novo protein design will revolutionize the ability to engineer protein-small molecule interactions, driving transformative advancements in fluorescence imaging, enzyme catalysis, and broader applications requiring precise molecular recognition.

Golden Field Office

The purpose of this Notice of Intent is to provide potential applicants advance notice that the Office of Energy Efficiency and Renewable Energy (EERE) intends to issue, on behalf of the Wind and Water Power Technologies Office (WWPTO), a Funding Opportunity Announcement (FOA) entitled ?U.S. Wind Manufacturing: Larger Blades to Access Greater Wind Resources and Lower Costs", Number DE-FOA-0001214. This FOA will support Research and Development (R&D) partnerships leading to innovative designs and processes for the manufacturing and assembly of wind turbine blades in order to facilitate deployment of the next generation of multi-megawatt wind turbines. Supported projects will develop cost-competitive integrated solutions that address the challenges of fabricating, transporting overland and assembling rotor blades longer than 60m, with design concepts scalable to greater lengths, and installing them at wind turbine hub heights of at least 120m. Multi-organizational teams including at least an original equipment manufacturer (OEM) turbine designer, a blade manufacturer and an installation/logistics firm are expected. The proposed FOA is intended to be forward-looking in addressing U.S. market dynamics and domestic manufacturing opportunities through innovative solutions to constructing and assembling larger blades directly applicable to mitigating U.S. transportation constraints. Awards under the FOA will support partnerships between DOE and research and development (R&D) teams, including manufacturers. The resulting designs must be manufacturable in the U.S. in accordance with the U.S. Manufacturing Plan to be submitted as part of the application. NO APPLICATIONS WILL BE ACCEPTED THROUGH THIS NOTICE. Please do not submit questions or respond to this Notice of Intent. Prospective applicants to the FOA should begin developing partnerships, formulating ideas, and gathering data in anticipation of the issuance of this FOA. The applicant must first register and create an account on the EERE eXCHANGE website. A User Guide for EERE eXCHANGE can be found on the EERE website https://eere-exchange.energy.gov/Manuals.aspxafter logging in to the system.

NIH

Significance to VA: Routine urine testing in surgical patients, either before or after surgery, is a low value practice and leads to overprescribing of antibiotics in the VA, which then leads to serious antibiotic-related side effects, such as Clostridioides difficile infections. Multiple national societies state that surgical patients without infectious symptoms should not have routine preoperative urine tests performed, and that not all fevers need urine testing to determine a cause, such as fever immediately in the postoperative state. Unfortunately, unnecessary urine testing occurs before 15-26% of VA surgeries overall, and before over 50% of certain high- risk VA operations. We have a track record of successfully implementing evidence-based practice guidelines about urine testing in VA settings. We hypothesize that implementation of our evidence-based intervention in the operative care line at 6 VA medical centers (VAMCs) will significantly decrease rates of urine testing and days of unnecessary antibiotics for surgical patients, both before and after operations. Our long-term objective is to improve Veteran care by ensuring that Veterans undergoing surgery receive only beneficial tests and treatments. Our work aligns with the [VA priority ‘Implement value-based care solutions’ and the core competency of Implementation Science by optimizing strategies to implement evidence-base practice.] This work also supports the Quintuple Aim and the Foundations for Evidence-based Policymaking Act. Innovation & Impact: Since 2013, we have been developing, testing, and disseminating an evidence-based intervention to reduce unnecessary urine testing, the “Kicking CAUTI” program. This intervention package includes a fast and frugal algorithm to help healthcare providers distinguish between UTI and bladder colonization, interactive teaching cases, case-based audit and feedback, and virtual learning collaboratives. This intervention boosts clinician autonomy, which is important to surgeons, but it has not yet been adapted for or tested in a surgical setting. Our intervention will decrease a low value practice and improve patient outcomes by preventing downstream consequences, such as antibiotic resistance and longer hospital stays. Specific Aims: Aim 1: Adapt our ‘Kicking CAUTI’ intervention to create a surgery-tailored intervention package informed by focus groups at six VA medical centers (VAMCs). Aim 2: Conduct a stepped wedge cluster randomized trial to evaluate the implementation and effectiveness of the tailored intervention package at six VAMCs. Aim 3: Evaluate the intervention in terms of [cost], acceptability, and barriers and facilitators to implementation. Methodology: We will conduct a hybrid type two effectiveness/implementation study. Our conceptual model is the Systems Engineering Initiative for Patient Safety (SEIPS) model. Aim 1: This work will be informed by focus groups with surgeons, nurses, and other operative care line personnel at six VAMCs. These stakeholders will help us tailor the Kicking CAUTI intervention to the surgical setting. Aim 2: We will conduct a stepped wedge cluster randomized trial. We will include patients undergoing surgery in these VAMCs, excluding certain types of surgery in which pre-operative urine testing is appropriate (urologic surgery). Clinical outcomes data including urinalysis, urine culture, days of antibiotics, will be extracted from Corporate Data Warehouse, in addition to surgical site infections, UTIs, length of stay and readmissions. Implementation measures will include adoption (time spent and cases discussed), penetration (providers reached), fidelity (use of intervention materials), [and dose]. Aim 3: Formative evaluations will occur through periodic reflections with local site champions and semi-structured interviews with key stakeholders at the six intervention sites. [The budget impact analysis will estimate the cost of implementing the intervention and direct healthcare costs saved by the intervention from the VA’s perspective.] Path to Translation/ Implementation: We will work with our operational partners (i.e., Antimicrobial Stewardship Task Force, National Surgery Office) to disseminate this intervention to other VAMCs.

Deaf Spotlight

Deaf Spotlight will offer a 3-week summer theater camp August 6-27, 2016 for 15- 20 middle and high school youth. They will learn all aspects of a theatrical production guided by two artists in residence. The goal is to engage youth who are hard of hearing or are signing hearing children of deaf adults. The project will culminate in a free performance of a play which the students will write and produce.