Grants

EAP

Capital Region Chamber Entrepreneurial Assistance Program Center 17-18

Albany-Schoharie-Schenectady-Saratoga BOCES

Capital Region Shared Student Transportation Project II

Portland Economic Investment Corporation

Capitalization of an investment fund to provide people of color and women who reside in Portland with startup capital.

Capitol Hill Housing Foundation

Nearly 90 percent of the residents living in the Capitol Hill EcoDistrict live in multifamily housing. Capitol Hill Housing, in partnership with the City, Capitol Hill Community Council and other neighborhood leaders, will engage renters living within the Capitol Hill EcoDistrict first in a voter registration and pledge to vote drive, and then as Building Ambassadors brought together at a 2016 Renters Summit to build community and inform the next wave of development coming to the Hill.

Capitol Hill Chamber of Commerce

With enormous & rapid change in Capitol Hill it is important that the neighborhood has the strongest possible leadership organization: sustainable, healthy & strong. We are proposing to work with community members & consultants to evolve the Chamber & a proposed Capitol Hill Business Improvement Area (BIA) to directly serve the Capitol Hill businesses, residents, nonprofits, & arts organizations in this very dense, challenging & rapidly growing neighborhood.

Sustainable Capitol Hill

Creation of a community tool library and fixer’s collective to provide items that people will be able to check out to take home or use in the workshop. There will be all sorts of items, e.g. ladders, drills, food dehydrators, ice chests, table settings, strollers, etc. The library will also host meetings and classes to help neighborhood residents to fix belongings, start DIY projects, and build community.

Hamden

Capitol Improvement Plan Preparation or Revision

Canaan

Capitol Improvements - Music Mountain and Wagnum Rd

Canaan

Capitol Improvements - Music Mountain Road

Capitol Theatre Foundation

Capitol Theatre Foundation is an active grantmaking foundation based in Chambersburg, PA. Focus: arts. Contact the foundation directly for current funding opportunities.

Beacon Hill International School PTA

The Capoeira in Schools project is a community collaboration offering free afterschool capoeira classes to elementary-aged students in Southeast Seattle. It will take place after school across winter, spring and fall quarters. Capoeira is an Afro-Brazilian martial art that combines music, dance and acrobatics. Capoeira promotes healthy physical activity and cognitive function to help students throughout their academic years and beyond. Afterschool classes will start January 2020 in the Welcome Table Christian Church located at 1322 South Bayview St, Seattle WA 98144.

Capoeira Life fiscally sponsored by Shunpike

Capoeira Life, our BIPOC, LGBTQ+, people w/disabilities, community-led group will provide 1 year of free weekly and monthly capoeira programs, and free capoeira participatory events to all members of public, especially underserved, at local recreational facilities, Seattle parks, community centers, schools, and other partner sites.

Capoeira and Arts Association of New England

Caporira Cultural Exchange Batizado and Workshops

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Capsid assembly is an essential step in production of an infectious herpesvirus, yet little is known on how the process begins and the protein oligomeric states and intermediate interactions required to complete the final mature capsid. Disruptions in capsid assembly result in aberrant capsids unable to assemble or package viral DNA, resulting in noninfectious virus. The major proteins involved in herpesvirus capsid assembly are generally conserved across alpha, beta, and gammaherpesvirus subfamilies which provides an opportunity to develop pan-herpesvirus therapeutics. Yet to date, little has been done to capitalize on this process; furthermore, most capsid assembly research focuses on alphaherpesvirus, HSV-1. This proposal focuses on understanding capsid assembly of gammaherpesvirus, Kaposi sarcoma herpesvirus (KSHV), the leading cause of cancer in HIV positive individuals. I will develop an in-vitro capsid assembly assay to monitor capsid kinetics and oligomeric states required for capsid nucleation and maturation. I hypothesize KSHV capsid assembly is a highly dynamic process requiring multiple conformations of capsid protein intermediates to generate a capsid capable of packaging a large DNA genome. I will purify KSHV capsid proteins via baculovirus expression and systematically determine the proteins required for capsid formation and kinetics via dynamic light scattering and negative stain electron microscopy. In addition, I will evaluate the oligomeric states of capsid proteins individually and protein intermediates to determine 1. The proteins required for capsid nucleation and 2. How KSHV scaffold oligomerizes to produce unique B-capsid morphologies. I further hypothesize that the divergence of SCP between subfamilies is a result of variations in the capsid assembly pathway. For example, it is thought SCP is not required for alphaherpesvirus capsid assembly but is required for gamma and betaherpesviruses. I hypothesize SCP is required for efficient C-capsid assembly, as loss of SCP results in decreased infectious virus and C-capsid formation in alpha, beta, and gammaherpesvirses; however, the exact mechanism is unclear and seems dependent on cellular environment. I will use the in-vitro capsid assemble assay and live virus mutagenesis to study the function of SCP in capsid maturation. I will utilize previously generated KSHV SCP null viruses to quantify capsid structural integrity with atomic force microscopy to determine at what stage capsid assembly stalls, as well as the role of phosphorylation on SCP’s function. These aims will highlight the similarities and difference between alpha and gammaherpevirus viruses, providing the evidence required for inhibitor development and a scalable in-vitro assay for testing inhibitors. I will develop a robust skillset in biophysical techniques which coupled with my expertise in molecular virology will allow me to successful complete these aims and develop the skills required to run my own independent research lab.

Seaport Museum New York

Captive Passage Programming

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Chemical separations are foundational to modern chemistry, yet traditional liquid chromatography-mass spectrometry workflows often fail to detect many isomeric and conformational features of biomolecules critical to metabolism, disease, and drug efficacy. To address these limitations, the Clowers Research Group (CRG) at Washington State University is advancing ion mobility spectrometry and mass spectrometry techniques, leveraging gas-phase ion chemistry and high-resolution separations enabled by Structures for Lossless Ion Manipulations (SLIM). SLIM technology’s extended cyclic separations and controlled gas environments allow for the resolution of isomers and intermediates that conventional methods frequently miss. To quantitatively capture isomeric heterogeneity in complex biological systems, the CRG is implementing tailored multiplexed ion strategies such as Phased Ion Mobility Spectrometry. This technique aligns SLIM separations with ultra-performance liquid chromatography timescales, reducing spectral ambiguity and improving the resolution of co-eluting isomers in diverse ‘omics applications. Complementing these strategies, the group is integrating gas-phase labeling techniques, including hydrogen-deuterium exchange (gHDX) and ozone-induced dissociation. These methods provide dynamic insights into molecular interactions by capturing solvent- accessible regions and chemically selective modifications, enhancing the characterization of isomeric and conformational states. The integration of tandem collision-induced unfolding with SLIM and gHDX adds another layer of analytical depth, enabling the isolation and detailed examination of intermediate protein structures. This approach reveals conformational transitions and solvent-accessible regions during unfolding, helping to quantify molecular stability and refine structural models of biopolymers. By combining SLIM-based separations, multiplexing strategies, and gas-phase labeling workflows, the CRG’s research program is redefining bioanalytical approaches. These innovations aim to enhance the detection of isomeric heterogeneity, reduce analytical errors, and provide new insights into metabolomics, lipidomics, and structural biology in support of public health outcomes. 1

NIA - National Institute on Aging

Poor social health (high loneliness, high social isolation, low social support) is associated with heightened risk for Alzheimer's disease and related dementias (AD/ADRDs). Theoretical models posit that social health's long-term effects on cognition result from cumulative risks associated with short-term, dynamic social processes. For example, loneliness may increase AD/ADRD risk by reducing healthy behaviors (physical activity) and increasing unhealthy behaviors (alcohol consumption), impacting momentary cognitive performance and variability – which, themselves, predict future AD/ADRD diagnosis. Digital biomarkers that capture short-term, dynamic associations between social and cognitive health hold promise to detect early clinical signatures of cognitive decline and identify personalized targets for AD/ADRD risk-modifying behavioral interventions. Three major gaps obfuscate mechanisms linking social and cognitive health, stalling digital biomarker development. First, there is a conceptual gap: theoretical models highlight the cumulative impact of daily social experiences in AD/ADRD-related cognitive decline, yet empirical research relies largely on cross-sectional or limited longitudinal designs ill-suited to capture this granularity. Second, there is a measurement gap: ecologically valid tools differentiating the ABCs of social health have yet to be validated for ecological momentary assessment (EMA), hampering interpretation of dynamic, within-person associations. Finally, there is a computational gap: AD/ADRDs are highly heterogeneous, yet current analytic approaches do not adequately accommodate individual differences in AD/ADRD pathogenesis. This project is strategically poised to address these gaps through three aims. We will (1) develop mobile assessments of social health; (2) delineate short-term cognitive impacts of daily social dynamics; and (3) generate individualized models of social determinants of AD/ADRD risk. We hypothesize that, within individuals, cognition will be reduced when social health is low. We further expect to identify social and behavioral mediators of within-person associations between social health and cognition, as well as multiple combinations of social risk factors that predict AD/ADRD risk, consistent with multiple pathways to AD/ADRD. We will test hypotheses in a sample of N=250 adults (45-74 years) who provide intensive longitudinal social and cognitive EMA data. Successful completion of study aims significantly advances measurement, mechanistic understanding, and early risk assessment in AD/ADRDs, with implications for reducing the burden of AD/ADRDs through behavioral intervention. Successful completion of study aims is innovative because it provides the field with novel, open-source EMA scales optimized to measure fluctuations in multiple dimensions of social health. Race and ethnicity will be representative of 2060 United States population projections, ensuring that products of our work–including open-source scales and dynamic modeling insights–will support accurate stratification of midlife risk as population demographics shift.

Maggie Osgood Library

Expand the Maggie Osgood Library Digital Repository (MOLDR) to include oral histories and bring the stories of Lowell and surrounding unincorporated areas to life.

NCI - National Cancer Institute

PROJECT SUMMARY CAR T cell therapy for solid tumors is hindered by a lack of tumor-specific antigens that are safe to target and homogenously expressed throughout the tumor, difficulty infiltrating the tumor due to dense tumor stroma, and suppression of CAR T cell function by the tumor microenvironment (TME). We plan to address these issues using novel meso-FAP CAR-TEAM cells that simultaneously target mesothelin, a solid tumor antigen that has already been proven safe to target in patients, and cancer-associated fibroblasts (CAFs), which inhibit T cell infiltration and suppress T cell function in the TME. The CAFs are targeted with T cell-engaging antibody molecules (TEAMs) secreted from the CAR T cells that bind to CD3 and fibroblast activation protein (FAP), which is highly expressed on CAFs. The TEAM allows for CAF elimination by CAR and non-CAR T cells in the tumor. We have already demonstrated that meso-FAP CAR-TEAM cells kill pancreatic cancer cells and CAFs in vitro, in vivo, and in patient-derived ex vivo models and have superior anti-tumor function compared to meso-CAR T cells alone. For the UG3 phase of this project, we will further optimize meso-FAP CAR-TEAM cells by determining the best mesothelin binder to use (SS1 vs. a novel binder developed by our lab), optimal route of injection (IV vs. IP) for targeting pancreatic tumors, and rationale drug combinations that address CAR T cell limitations in solid tumors. We will improve antigen density using an ADAM17 inhibitor (INCB7839) to prevent mesothelin cleavage from pancreatic cancer cells, optimize CAR T cell killing and persistence using ibrutinib to polarize meso-FAP CAR T cells to a Th1/Th17 phenotype, and further prevent suppression by the tumor microenvironment using a PD1 inhibitor (pembrolizumab). These drugs will be singly combined with meso-FAP CAR-TEAM cells to determine which best promotes efficacy in our preclinical models. Collectively, these results will inform the design of a phase I clinical trial for pancreatic cancer patients with advanced disease. During the UH3 phase, we will determine the safety and tolerability of meso-FAP CAR-TEAM cells. We have chosen pancreatic cancer as our first solid tumor target due to the dismal prognosis of the disease, the high percentage of patients with mesothelin-expressing tumors, and the known role of CAFs in promoting tumor growth. While our primary objective will be to determine safety, we will also monitor patient outcomes (progression and survival) while performing correlative studies to determine CAR T cell phenotype and function. We will also monitor the tumor and tumor microenvironment for mechanisms of response or resistance, such as changes in antigen expression and immunosuppressive cells. Overall, this project will develop a novel CAR-TEAM design to target a solid tumor and its microenvironment while optimizing the trial design through rigorous preclinical testing. If successful, the meso-FAP CAR T cell product could be directly applied to other mesothelin-expressing solid tumors and the knowledge gained from the UG3 phase will inform on the critical aspects of CAR T cell function to optimize prior to initiating a clinical trial.

Chicago Department of Transportation

FFY 2025 STATE/LAKE LOOP ELEVATED

NSF

Access to the genetic information encoded in DNA must be both rapid and under tight control so that a cell can readily adapt to its environment, or rapidly respond to growth signals. One regulatory mechanism that is used in nature is to poise the protein machines that access genetic information at the start of genes, waiting to initiate the process of converting the encoded information into molecules that execute cellular functions. Chemical modifications of these ready-to-go proteins exert timely control over cellular responses to stimuli by dictating the efficiency with which genes are activated. For this project, the investigator will push the boundaries of current technologies to explore the structural responses to chemical modifications that trigger release from pausing and entry into efficient decoding of genetic information. This program addresses a significant gap in our knowledge of how gene expression is regulated. This program will train junior scientists at multiple education levels to seek fundamental insight into the systems and processes from biochemistry, using the principles and quantitative laws from the physical sciences. Among other outreach efforts, the investigator will bring undergraduate students from different schools to Penn State for research opportunities that will enhance their career potential in science and engineering fields. To achieve this project’s objectives, new experimental methodology will be implemented for nuclear magnetic resonance (NMR) spectroscopy of highly flexible proteins. While protons are relatively easy to observe by NMR, the PI has shown that the comparatively more challenging direct-detection of carbon yields more quantitative and complete information for intrinsically disordered polypeptides. Recently, the PI used this technique to demonstrate how serine phosphorylation of RNA polymerase II provides a structural switch that plays a role in regulating the critically important enzyme. RNA Polymerase II pauses at the start of genes before entering into productive elongation and these phosphorylation events are associated with release from the paused state. The PI will now broaden the characterization of pause release by investigating threonine phosphorylation on a required co-regulator of RNA polymerase II, named the DSIF complex, which is a second necessary step for pause release. The phosphorylation patterns on RNA Polymerase II change throughout the process of RNA elongation, so this project will extend characterization of serine phosphorylation to model each of the relevant states in an RNA production cycle. Finally, lysine amino acids in a specific region of RNA polymerase II also acquire methyl groups while the enzyme is active on a subset of genes. These modifications can exert combinatorial control with the previously characterized phosphorylation. Therefore, experiments will be performed to test the hypothesis that addition of methyl groups to the amino acid lysine also induces structural transitions, akin to those the PI has observed in association with phosphate incorporation. As a result, this research and associated training activities will yield fundamental, molecular level insights that provide critical molecular insights into gene regulation. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences. 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.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Heart disease is a leading cause of mortality among cancer survivors, significantly impacting over 9% of the 16.9 million adult survivors in the United States. These survivors develop heart conditions post-treatment due to the cardiotoxic effects of chemotherapy agents like anthracyclines. Anthracyclines, such as doxorubicin, are potent chemotherapeutic agents used extensively in cancer treatments. They are administered in approximately 60% of breast cancer and 70% of childhood cancer cases. However, they cause acute cardiotoxicity in about 11% of patients, with detrimental cardiac effects persisting for up to 40 years in childhood cancer survivors. Current cardioprotective therapies, including dexrazoxane, have demonstrated limited long-term efficacy and raise concerns about potential interference with doxorubicin's antitumor effect. This highlights a significant gap in effective cardioprotective therapies due to an insufficient understanding of the molecular mechanisms underlying anthracycline-induced cardiotoxicity (AIC). Recent advancements in human induced pluripotent stem cell- derived cardiomyocytes (iCMs) offer unprecedented opportunities to model human cardiac diseases at an individual level, providing a novel avenue to explore the mechanisms of AIC. Leveraging the iCM model, combined with CRISPR interference/activation (CRISPRi/a) genetic screens, our preliminary studies have identified that inhibition of Carbonic Anhydrase XII (CA12) mitigates AIC in iCMs and in mice treated with doxorubicin. CA12 is involved in regulating intracellular pH and metabolism, potentially enhancing lactate production through glycolysis. Our findings suggest that doxorubicin upregulates glycolysis in iCMs via CA12 activation, leading to increased lactate production and subsequent histone lactylation, specifically at H3K18la - a newly characterized epigenetic modification influencing gene expression and potentially contributing to cardiomyocyte dysfunction. We hypothesize that cardiac-specific knockout of CA12 will reduce doxorubicin- induced glycolysis and lactate production, thereby protecting cardiac function by preventing the activation of cardiac dysfunction genes via histone lactylation. In Aim 1, we will investigate the role of CA12-mediated glycolysis in AIC by assessing whether inhibition of CA12 can protect against AIC in iCMs derived from patients who have experienced doxorubicin-induced cardiotoxicity (DoxTox patients) and in cardiomyocyte-specific CA12 knockout (Car12 cKO) mice. In Aim 2, we will explore the role of glycolysis-mediated histone lactylation in AIC and its relationship with CA12 by examining how increased lactate production leads to histone lactylation at H3K18la, epigenetically activating cardiomyocyte dysfunction genes. Ultimately, these findings have the potential to improve the long-term cardiovascular health of cancer survivors by informing the development of safer chemotherapy regimens and adjunctive therapies that protect cardiac function, thereby addressing a critical unmet need in cardio-oncology.

NHLBI - National Heart Lung and Blood Institute

Project Summary Cystic fibrosis (CF) is a genetic disease causing premature death, primarily due to respiratory failure from increased inflammation and chronic infections. While therapies targeting the dysfunctional protein channel have improved lung function and mucus clearance, infection remains a significant problem. This proposal investigates how impaired microtubule (MT) dynamics and intracellular transport, exacerbated by reduced carbonic anhydrase (CA) expression, contribute to increased bacterial adhesion in CF. The central hypothesis is that reduced CA expression disrupts MT dynamics, leading to impaired intracellular transport and accumulation of pathogen-binding targets on cell membranes. The approach will use advanced live cell imaging, biochemical assays, proteomics, and microbial adherence studies to test hypotheses across three specific aims: 1) Determine the role of CA2 and CA12 in intracellular transport and membrane organization; 2) Identify the binding target and mechanism for increased bacterial adhesion in CA-deficient airway epithelia; and 3) Assess the roles of MTs and CA in the ability to eradicate Pseudomonas aeruginosa among people with CF, determining in vitro response to MT- and CA-targeted agents. This research will provide new insights into the cellular mechanisms of infection in CF and could identify novel therapeutic targets to improve infection control. The significance of this study lies in its comprehensive approach to understanding and addressing infection in CF, which can be applied to other diseases involving defective intracellular transport and cytoskeletal dynamics. This project will also serve as an excellent vehicle for the applicant’s development into an independent investigator. Investigations will be performed in an environment with an established history of successful mentorship of junior faculty to independence. The applicant’s long-term career goal is to become a leading, independent investigator with a translational lab studying cellular mechanisms driving infection and inflammation in the lungs, with a specific focus on host-microbial interactions that modify the landscape of microbiota within the airway. With the support of this award, the applicant will 1) build technical skills in advanced imaging techniques, 3D model systems, and bioinformatics, and 2) develop expertise in interpreting data and translating findings to clinical therapeutics. Future independent studies will focus on the relevant pathways and targets affected by CA and MT disruption to identify possible therapeutic interventions that can be tested in pre-clinical, and ultimately clinical, models.

NHGRI - National Human Genome Research Institute

Nest Genomics has created a software platform to launch, implement, and scale longitudinal genomic programs. It supports patients with hereditary syndromes from risk identification to long term management following the latest guidelines for disease management. As a personalized platform built to support and empower patients over time, Nest is well positioned to address challenges around family sharing and cascade testing. A use case focused on cardiac diagnoses has not been developed nor has the functionality to share and communicate genetic risk information. The objective of this Phase I STTR is the development, adaptation, and refinement of the Nest platform for risk communication and disease management in families with hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition, using a recursive process between Nest Genomics, Virginia Commonwealth University (VCU), and University of Iowa (UI). The technical merit and feasibility of the proposed research and development efforts will be achieved through three aims: Aim 1: Develop HCM content in the Nest platform. Nest Genomics and its academic partners, VCU and UI will collaborate to develop storyboards for patients with HCM and their family members. Storyboards will include guideline driven action items including clinical screening (e.g., echo, ekg), information for affected persons and at-risk relatives. Aim 2: Build Family Sharing Functionality. Nest Genomics, VCU, and UI, will collaborate to develop family sharing functionality within the Nest platform. These developments will focus on integrating the patient’s pedigree information with their user contact list to develop a family sharing plan. The family sharing plan will allow users to easily identify at-risk relatives and select and share authoritative health information (including genetic test reports) with them. The platform will guide relatives through their genetic risk information and facilitate next steps, including scheduling genetic counseling and/or genetic testing and will facilitate feedback loops to support sustained family engagement. Aim 3: Establish usability and acceptability among families with HCM (patient-relative dyads) and healthcare providers. An iterative “think aloud” process will be used to gather feedback from a representative group of participants (n=20 dyads) and 15 genetic healthcare providers. Data will be analyzed to assess usability and acceptability of the content and family sharing functionality. This user feedback will guide revisions of the platform until an acceptable, user-friendly iteration is achieved. Communication of HCM risk among family members is a critical step to ensure relatives have the option to be screened and treated prior to the development of life-threatening complications. Successful completion of this Phase I project will demonstrate feasibility of the product in a diverse population and provide the functionality and data to advance, test and commercialize the product in a Phase II project. This project also provides pilot data for future R-level studies evaluating and comparing effectiveness of the tool in improving communication and cascade screening in families.