Ohio State University

NIH Research Projects · FY 2025 · 2025-09

Abstract / Project Summary Stroke is a significant contributor to death and disability worldwide. With increased survivability due to advancements in clinical treatments, 35-50% of patients suffer from long-term neurological deficits in learning and memory termed Post-Stroke Cognitive Impairment (PSCI). Utilizing the middle cerebral artery occlusion (MCAO) model of focal ischemia, we can investigate chronic timepoints post-stroke to ameliorate cognitive deficits. Our lab has targeted the transient receptor potential melastatin 2 (TRPM2) channel as a potential locus of therapeutics. As a Ca2+ permeable non-specific cation channel, TRPM2 is activated in periods of oxidative stress, such as in stroke, and contributes to both cognitive and synaptic dysfunction. Indeed, data obtained in the laboratory before I joined demonstrates that acute and delayed administration of a TRPM2 channel antagonist improves synaptic and cognitive recovery following experimental stroke. TRPM2 is in multiple cell- types throughout the brain, and I seek to investigate the neuronal component of TRPM2 by utilizing genetic animal models and adeno-associated viruses (AAVs) to conditionally knockout TRPM2 from neurons. In aim 1, I hypothesize that a neuron-specific knockout rescues long-term potentiation (LTP) and behavioral deficits up to 30-days post-stroke. In aim 2, I seek to investigate the downstream mediators of TRPM2. Data suggests that in periods of hypoxia, a positive feedback loop is initiated; TRPM2 is activated and the kinase PKC is then recruited to the area where it phosphorylates TRPM2 at serine 38 further enhancing activation of the TRPM2 channel. Calcineurin activates (dephosphorylates) glycogen synthase kinase 3-beta (GSK-3) after TRPM2 activation. Evidence shows that dephosphorylated GSK-3 is responsible for the internalization of a-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors ultimately leading to a decrease in LTP. A final player in this complex signaling pathway is regulator of calcineurin 1 (RCAN1), which binds to calcineurin and increases its activity at key phosphorylation sites. Due to RCAN1’s role within the calcineurin-GSK-3β signaling pathway, RCAN1 is implicated in the bidirectional regulation of hippocampal synaptic plasticity. Data further suggests a potential link between PKC and the downstream actions of RCAN1 are mediated by TRPM2 channel activation. In aim 2, I hypothesize that decreasing RCAN1 and GSK-3 expression will rescue LTP deficits. This training plan will build methodological skills in electrophysiology, biochemical analyses, and more culminating in multiple manuscripts. It will also foster the growth of my career attending seminars focused on women in STEM, networking to further the advancement of women throughout academia, and mentoring the next generation of scientists. I have chosen Dr. Paco Herson as my mentor at The Ohio State University because they maintain incredibly high standards in state-of-the-art facilities that will ensure my development as an academic neuroscientist.

NIH Research Projects · FY 2025 · 2025-09

Project Summary There is a critical need to intervene with individuals affected by substance use disorder (SUD) earlier in their trajectory, even before they present to a location where screening or care could be possible. Rapid diagnosis and linkage to treatment (secondary prevention) is a cornerstone of any epidemic response but often very delayed for SUD. For communicable infectious diseases (ID), health departments employ disease intervention specialists (DIS) skilled in outreach to underserved and disproportionately affected populations identified via social contacts, who once located, disclose their own contacts, yielding “snowball” chain-referral for the most direct, rapid, and proactive approach to identify affected, but undetected, populations. SUD also exists within social networks and substance exposure spreads like contagion, but the DIS paradigm has not been adapted to the problem of SUD. With support from Funding Option B (develop, implement, and rigorously evaluate strategies), we will (AIM 1): Develop and implement promising operational models for adapting the conventional ID DIS model to provide secondary SUD prevention: In close collaboration with health department partners, we will create three service models: 1) Overlay of SUD intervention on current ID DIS: systematically screen clients (already being identified by ID diagnosis or exposure) for concurrent SUD; 2) SUD DIS: SUD specific DIS elicit social contacts with potential SUD from index clients with SUD who are identified in collaboration with other local service agencies; and 3) SUD DIS with peer-support: Peers embedded with the SUD DIS team. Model 1 will be operated separately from the SUD DIS program, with randomization by day to Model 2 or 3. In all 3 models, DIS will provide secondary prevention to those SUD screen+ (i.e., high risk score on NIDA-Modified ASSIST) and not already in care. (AIM 2): Rigorously evaluate models for incorporating SUD prevention into DIS programs. We will compare program-level outcomes using (i) data from DIS records, (ii) summary intake counts from regional SUD treatment centers, (iii) time and motion observations of DIS activities, and (iv) qualitative interviews with stakeholders (clients and staff) about the DIS program. We will also prospectively observe clients (n=400 each DIS program, for total n=1200) receiving DIS intervention who consent to research to enable comparison of the effectiveness of SUD secondary prevention provided by the different DIS program models. Assessment: Self-report at baseline (0),1, and 6 months, complemented by review of health records (via release of information) and vital statistics (i.e., mortality). Primary Outcome: severity of drug use at 6 months post initial DIS interview. Key Secondary Outcomes: participant characteristics; healthcare/service utilization; alcohol use; and overdose. This innovative, high-impact investigation will be the first to use this well-established public health approach, capitalizing on social networks, to offer early and more specifically targeted secondary prevention for SUD. Results will vastly improve public health practice, program planning, policy, and future intervention.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The goal of this application is to support Lei Wang, Ph.D., as a Research Scientist and Research Software Specialist at The Ohio State University. He will collaborate with Dr. Lang Li and develop an active learning collaborative platform for language models to support several NIH-funded research programs (R01LM014199, P30HD106451, and U01CA248240). The proposed AL-MedLit platform is the first software that allows language models and human experts to collaborate, ensuring the improvement of knowledgebase development and reduction of the curation cost. The innovative algorithms, including both conventional uncertainty sampling schemes and novel sampling schemes such as positive sampling, negative sampling, and sample calibration, will be implemented in the platform to facilitate the evolution of language models. This Research Software Engineer award would allow 3 years of funding to fully maintain Dr. Lei Wang’s dedicated efforts toward developing an innovative active learning platform for pharmaco-informatics research programs. In particular, he will expand his skill set, especially in the rapidly evolving fields of natural language processing and artificial intelligence and its applications in pharmaco-informatics research. Results will be broadly disseminated through local and national meetings as well as peer-reviewed journal manuscripts.

NIH Research Projects · FY 2025 · 2025-09

Nutrition insecurity (inclusive of food insecurity + poor diet quality) is a fundamental non-medical, health- related social need that impacts >20% of pregnant women and up to 50% of individuals with pregestational diabetes in the United States. Nutrition insecurity has devastating health consequences for the >100,000 pregnant women with pregestational diabetes (type 1 or 2) and their exposed infants every year for whom a healthy diet is critical. Pregnant women with pregestational diabetes and nutrition insecurity are more likely to experience poor glycemic control, and as a result, adverse pregnancy outcomes. The risk of these adverse health outcomes increases when glycemic control is not achieved and social needs go unaddressed. Enhancing healthy food access and providing nutrition education–i.e., building “nutrition security”–is critical to improving outcomes for pregnant women with diabetes and poor glycemic control. Our transdisciplinary team designed NOURISH: a theory- and evidence-based and collaborative healthcare-community partnership to enhance healthy food access, provide nutrition education and support, and address unmet social needs to improve glycemic control and pregnancy outcomes for high- risk pregnant women with pregestational diabetes, poor glycemic control, and food insecurity. We propose the tripartite sustainable NOURISH intervention: 1) weekly nutritious produce home delivery by the Mid- Ohio Farmacy (MOF+), 2) monthly clinic-integrated diabetes, nutrition, and culinary group education by the OSU Cooperative Extension’s Dining with Diabetes Program (DWD), and 3) continuous community health worker-led social needs assessment and support by the Health Impact Ohio Central Ohio Pathways Hub (Hub). Our central hypothesis is the combined NOURISH intervention (MOF + DWD + Hub) versus standard care will achieve glycemic control (hemoglobin A1c <6.5% by delivery), prevent adverse pregnancy outcomes (gestational weight gain and neonatal morbidity), and improve diet quality and nutrition security. We will randomize 174 eligible pregnant women (87 NOURISH, 87 standard care) ≤14+6 weeks’ gestation with pregestational diabetes, poor glycemic control (A1c ≥6.5% at randomization), and food insecurity. We will accomplish three specific aims: 1: use a pragmatic randomized controlled trial to test the effect of NOURISH—enhanced nutrition provision (MOF+), nutrition and diabetes education (DWD), and social needs referrals (Hub)—on improving glycemic control and pregnancy outcomes; 2: use cost- effectiveness analysis to assess the NOURISH intervention’s value relative to standard care; and 3: use process evaluation to characterize intervention and contextual factors influencing uptake, effectiveness, and sustainability of the NOURISH intervention. NOURISH is a scalable and mutually beneficial healthcare-community partnership to improve nutrition security, glycemic control, and outcomes for pregnant women living with diabetes.

NIH Research Projects · FY 2025 · 2025-09

Abstract Carbapenems are among our most precious broad-spectrum antimicrobial drugs because they are the therapy of choice for life-threatening invasive bacterial infections. Unfortunately, the increasing frequency of use of carbapenems has led to the emergence and dissemination of carbapenem-resistant Enterobacterales (CRE) in human healthcare where heavy selection pressure and population-dense environments favor the emergence and spread of highly resistant strains. CRE are now also emerging as an important antimicrobial resistance threat in veterinary medicine. Healthy companion animals in the community can become asymptomatically colonized with CRE in their enteric microbiota through normal contact with food, other animals, humans, or the natural environment including surface waters. If these animals later require veterinary care for unrelated health conditions, there is risk that their CRE colonization will be unrecognized and that the CRE will subsequently contaminate the hospital environment where other patients and staff may then be exposed. The emerging threat of CRE to hospitalized veterinary patients has been described for multiple outbreaks. Unfortunately, accurate and cost-effective rapid screening tests that can provide a result in time for colonized patients to be identified and appropriately managed during hospitalization to prevent transmission are not available. These tests will be needed in order to implement effective surveillance and CRE infection control programs in veterinary settings. We are proposing to validate a rapid screening test for CRE colonization, implement for surveillance in our hospital patient population, and share the results with the veterinary community regarding the identification and management of CRE colonized veterinary patients. To accomplish this, we propose to validate a LAMP assay as a screening test for patient CRE colonization using both experimental and observational methods. Our experimental method will utilize canine feces spiked with CRE at multiple dilutions to establish the ability and sensitivity of the LAMP assay to detect CRE in fecal samples. Observational data will be generated to validate the LAMP assay by testing OSU VMC patient fecal swabs in parallel with selective culture, and by testing blinded samples of known status provided by a collaborator. Once validated, we will then implement the LAMP assay for ongoing surveillance of CRE colonization in our patient population. That data on patient CRE colonization will allow us to make patient management and intervention decisions within 24 hours of patient admission. We will then disseminate information regarding LAMP assay performance and our implementation to other Vet-LIRN laboratories and to the veterinary community through scientific meetings and continuing education.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Inherited retinal disease (IRD) represents a molecularly heterogenous group of chronic blinding conditions that impact 5.5 million people worldwide, stemming from mutations in over 240 genes. The retina spans from the anterior barrier of inner limiting membrane (ILM) to the light-sensing photoreceptors posteriorly. The retina is positioned immediately anterior to the retinal pigment epithelium (RPE), which is critical for recycling the light- sensitive opsins in the apposed retinal photoreceptors as well as for paracrine support. Recently, the RPE has been elegantly shown to produce insulin locally, nearby the retina, which itself is rich in insulin receptors. Voretigene neparvovec (Luxturna) was the first FDA approved gene therapy for IRD treatment, treating patients with homozygous mutations in RPE65, but constituting just 0.5% of IRD patients. It works by introducing a functioning copy of RPE65 with an adeno-associated virus (AAV) injection under the retina. This creates a temporary retinal detachment but penetrates the anterior ILM barrier and focusses gene transduction in the RPE, where RPE65 primarily functions. Despite its initial success, considerable doubts remain in the field as many patients are challenged by ongoing chronic retinal/RPE atrophy in the area of subretinal bleb formation for AAV administration, causing subsequent treatment failure after initial success. Two proposed failure mechanisms include (1) immune response to residual vector, and (2) physical shearing forces on diseased and delicate photoreceptors during retinal detachment creation with subretinal delivery of AAV. Thus, the aims of the enclosed grant are constructed to test a novel AAV administration approach that combines both a pre- retinal (rather than subretinal) approach with adjuvant insulin administration to accelerate uptake of AAV into retinal cells. In this way, we propose that AAV uptake into retinal cells can be accelerated to the order of minutes, allowing for removal of residual AAV after transduction during surgery, avoidance of intentional retinal detachment, and prevention of inflammation from residual AAV. If successful, this gene agnostic approach could be quickly adopted to treat virtually any inherited retinal disease, and extended to nonviral approaches for larger genes. These studies will be carried out with strong support of the Ohio State Gene Therapy Institute and Department of Ophthalmology. The two lead mentors are R01 holding experienced principal investigators, with decades of experience directing laboratories that focus on retinal cell biology and central nervous system gene therapy, respectively. They have each successfully mentored multiple junior faculty members to R01 NIH funding. With their targeted mentorship and that of a separate Advisory Team, as well as educational coursework and intentional integration into the scientific community, support from this K08 will help transition Dr. Mendel from retinal cell biologist and surgeon to expert retinal gene therapy investigator.

NIH Research Projects · FY 2025 · 2025-09

Long-term excessive alcohol consumption leads to a significant prevalence of alcoholic cardiomyopathy (ACM) that is characterized by impaired cardiac function (heart failure, HF) in the absence of other cardiovascular diseases. During the COVID-19 pandemic, increased alcohol consumption due to social isolation has magnified the serious problem. Clinically, ACM is a leading cause of non-ischemic dilated cardiomyopathy increasing mortality and morbidity and puts a tremendous economic burden on our healthcare system. Sarcoplasmic reticulum (SR) Ca2+ ([Ca2+]SR) mishandling is known to play a key role in cardiac hypertrophy and HF development. The SR Ca2+ pump, SERCA2, is essential in [Ca2+]SR handling and reduced SERCA2 expression leading to depleted [Ca2+]SR load is a hallmark of HF. However, failed clinical trials of SERCA2 gene therapy in HF patients suggests that increasing the abundance of SERCA2 per se is insufficient to reverse HF. Although alcohol abuse is a significant risk factor for HF, it can take many years for an alcoholic individual undergoing adaptive cardiac changes with normal function to reach the point of ACM. The underlying mechanisms remain unclear to date. The goal of this proposal is to fill this knowledge gap by exploring a previously unknown mechanism of alcohol activated JNK2 acting as a driver of ACM onset. Our pilot findings show that JNK2, but not JNK1, is critical in alcohol-caused cardiac remodeling via a dynamic regulation of JNK2α variants in augmented SERCA2 pump activity (adaptive) followed by suppressed SERCA2 transcriptional activity (maladaptive). Our lab recently reported a critical role of JNK2 (not JNK1) in enhanced [Ca2+]SR uptake/load via enhanced SERCA2 activity. Aim 1 here will detail how JNK2 interacts/phosphorylates SERCA2 to augment its pump activity as an adaptive response to long-term alcohol exposure. JNK2 has multiple splicing variants (i.e. α, β). We identified that α1, α2, β2 (but not β1) are predominantly expressed in the human heart. And we found significantly increased JNK2α2, but reduced JNK2α1 correlated with reduced SERCA2 expression in human ACM LVs, while increased JNK2α2 suppressed the SERCA2 promoter activity, which is likely due to hypermethylated SERCA2 promoter through JNK2α2-upregulated DNA methyltransferase DNMT1 transcription activity. Thus, Aim 2 will define how JNK2α2 suppresses SERCA2 expression and onsets ACM, and test the translational potentials of blocking the JNK2α2 actions as an anti-ACM therapeutic strategy. Our multi-discipline team will use a unique combination of cutting-edge approaches (protein-SR-myocyte-heart-animal, in vitro to ex vivo to in vivo) including a novel battery of cardiac-specific JNK2α2 mouse models (JNK2act, MKK7D, MKK7D-JNK2dn, JNK2dn), in vivo gene transfer, and biochemical/proteomic/CUT&Tag-Seq/bioinformatics analyses to systematically fulfill the two Specific Aims. The scientific premise of this innovative proposal is strong given the integration of targeted functional measurements and paired with mechanistic experimental designs along with appropriate alternative approaches. Anticipated outcomes from the mechanistic and proof-of-concept translational studies will reveal causal role of JNK2α in ACM onset and provide translational insight into modulating JNK2α variants as a prospective anti-HF intervention.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Alcohol use disorder (AUD) affects millions and is one of the leading causes of preventable death worldwide. Existing pharmacotherapies for AUD have limited efficacy and variable treatment response. There is an urgent need to expand pharmacologic treatment options for AUD and to better understand how and for whom new medications exert their therapeutic effects. Suvorexant – a dual receptor antagonist of the orexin system, FDA- approved for insomnia- has been identified as promising novel addiction pharmacotherapy that may target stress-related drinking and the negative reinforcement cycle of AUD. The MPIs have recently completed two studies designed to advance the translation of suvorexant (SUV) for AUD including a randomized, double-blind, placebo-controlled clinical trial (RCT) with repeat lab assessments in non-treatment seeking individuals with current AUD (R21AA030097; NCT05656534). The R21 study demonstrated that 10mg of nightly SUV was well- tolerated and associated with acute and sustained reductions in well-defined laboratory assays of exaggerated stress reactivity: i.e., startle eyeblink potentiation to unpredictable threat. Preliminary data also revealed that SUV was associated with changes in subjective stress levels and heavy drinking days. There is now mounting animal and human evidence that suggests that the orexin system is critically involved in stress-related alcohol use. The overarching goal of the current R01 proposal is to further test whether SUV can be used as a novel therapeutic for AUD and stress-related drinking. We will conduct a double-blind, placebo-controlled, between- subjects RCT with 250 treatment-seeking individuals with current AUD. To optimize clinical translation, this study will simultaneously assess treatment: 1) efficacy; 2) mechanisms; and 3) prediction. Participants will be randomized to either 8-weeks of 10mg of SUV (nightly oral capsules) or placebo (PBO) and complete baseline, mid-point, and end-point laboratory assessments of stress reactivity and other competing mechanisms of interest (e.g., alcohol cue reactivity). Throughout the RCT, daily reports of stress, alcohol craving and consumption, sleep, and medication compliance will be captured via smartphones. Wrist-worn sensors will measure objective sleep metrics and real-time alcohol consumption, while blood plasma will yield biomarkers of recent alcohol use and SUV concentration. This innovative, comprehensive design will allow for a well-controlled test of whether nightly SUV decreases the proportion of heavy drinking days (PHDD; primary) and a variety of secondary subjective and objective measures of alcohol consumption compared with PBO (Aim 1). We will also investigate how SUV works by testing whether SUV decreases objective and subjective indices of stress and stress-related alcohol craving and consumption (Aim 2). Lastly, we will identify whom SUV works for best and whether multimodal markers of heightened baseline stress reactivity can be used to create a predictive tool for future SUV treatment assignment (Aim 3). Findings from this study will provide critical knowledge on a novel therapeutic for AUD and help to develop a prospective SUV treatment assignment strategy for optimizing AUD outcomes.

NIH Research Projects · FY 2025 · 2025-09

The National Center for Advancing Translational Sciences (NCATS) strives to develop and promote clinical and translational science (CTS) innovations to reduce, remove, or bypass costly and time-consuming bottlenecks in clinical and translational research (CTR) in order to speed up the delivery of new drugs, diagnostics, and medical devices to patients. Data science, as a primary approach in CTS, has demonstrated broad impact on CTR. This impact stems from the fact that data science is composed of several disciplines, including biostatistics, bioinformatics, clinical informatics, computer science, implementation science, learning health systems, pharmacometrics, systems pharmacology, etc. Data science is crucial in every step of the CTS process. Because of the insufficient number of personnel adequately cross-trained in CTS and data science and the need for future leaders in these fields possessing strong team science skills, we propose a Clinical and Translational Data Science (CTDS) T32 Postdoctoral Training Program. The Ohio State University (OSU) Clinical and Translational Science Institute (CTSI) is positioned to lead this CTDS post-doctoral training program. Leveraging strengths from both clinical science and data science at OSU, CTDS has four themes, namely AI in Digital Health, Biostatistics and Population Health, Translational Genomics, and Translational Pharmacology. Our CTDS T32 Postdoctoral Training Program has three training goals: (1) to recruit, rigorously educate, and inspire post-doctoral fellows with various training backgrounds to drive discoveries and innovations in clinical and translational data science; (2) to foster a learning environment grounded in interdisciplinary mentorship excellence focused on trainee success and satisfaction; and (3) to develop future clinical and translational data science leaders who advance and promote human health through discovery, teamwork, science communication, and sustained engagement. Outcomes indicative of successful training include: every trainee shall receive training in at least one of four CTDS themes; every trainee shall receive training in at least two CTS core knowledge components among pre-clinical research, clinical research, clinical implementation and public health; every trainee will demonstrate the ability to work on team science and in a team-based research endeavor; and the program will ensure trainees are selected from highly qualified scholars from multiple disciplines to promote broad participation in clinical and translational data science. In this T32, we will fund four trainees a year, three through this T32 and one from institutional support. Each trainee will receive two-year funding support.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Vitamin C (VC) insufficiency is surprisingly common, affecting approximately 42% of people (about 139 million individuals) in the United States, and it is likely a hidden factor contributing to lung disease. Previous clinical trials have linked VC deficiency to increased severity of respiratory disease and pneumonia. However, the exact molecular mechanism behind VC's role in the lung remains incompletely known. Understanding the impact of VC deficiency is critical for mitigating respiratory disease severity; further, revealing the molecular mechanism behind VC’s function may lead to identification of novel therapeutic targets in the lung. Previous work from our lab and others showed that VC levels can alter cell fate decisions by functioning as a cofactor for the Ten-Eleven Translocation (TET) family, enzymes responsible for DNA demethylation. We previously demonstrated that VC promotes B cell differentiation by increasing the expression of transcription factor BLIMP1 through TET-mediated enhancer demethylation. In T cells, BLIMP1 is required to establish lung- specific tissue resident memory CD8 cytotoxic T cells (CD8 TRM) essential for immunity against respiratory pathogens, including influenza A virus. Thus, we hypothesize that VC is required for the differentiation and homeostasis of lung TRM by promoting TET-dependent BLIMP1 expression. We will restrict VC deficiency or TET deficiency to CD8 T cells and assess their ability to differentiate into CD8 TRM and to provide lung immune protection against influenza rechallenge. We will profile DNA methylation patterns to define TET activity involved in establishment of lung CD8 TRM. Further, we will determine if VC and TET regulate BLIMP1 expression and if BLIMP1 expression can rescue TRM phenotypes observed in the VC- or TET-deficient CD8 T cells. The completion of this proposal may reveal factors that help mitigate lung damage associated with severe respiratory diseases. It may also identify specific genes and DNA elements that can be targeted to potentiate lung CD8 TRM responses for vaccine design. These research goals will be accomplished by the applicant, Ms. Bella Lee, in the context of an individualized training plan developed by the applicant and her mentorship team. Specifically, her training plan places special emphasis on bridging lung physiology, epigenetics, and immunology; scientific communication with both peer and public audiences; and ethics training tailored to the era of artificial intelligence to form the foundation of her physician-scientist career. Taken together, the proposed work will 1) demonstrate one of the elusive cellular and molecular mechanisms of how VC mediates lung protection and 2) advance Ms. Lee’s scientific acumen, technical expertise, and professional network as she pursues an independent physician-scientist research career in barrier immunology.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Irritability is common in early childhood and declines as children approach middle childhood. Irritability that persists into middle childhood affects up to 20 percent of youth and is a marker of risk for psychiatric problems. To date, the study of irritability has focused on personal (e.g., parenting style) and genetic risk factors for irritability with little attention focused on the contribution of exogenous, environmental factors, such as prenatal exposures to neurotoxicants. This K23 application presents a research and training plan that will support the applicant, Dr. Mariah DeSerisy, on a path towards becoming an independent investigator working at the intersection of child mental health, environmental epidemiology, and neuroimaging. The activities in this application build on Dr. DeSerisy’s prior training and are set in a resource-rich environment which will allow her to further develop her skills in: (1) analyzing effects of polycyclic aromatic hydrocarbons (PAH) using advanced epidemiologic methods, (2) developmentally sensitive, multi-informant/method assessment tools for early childhood irritability, (3) longitudinal modeling of high-dimensional data using causal inference approaches, (4) network-based functional connectivity magnetic resonance imaging (MRI) data analysis, and (5) ethical conduct of research with vulnerable populations. By combining MRI and environmental epidemiology, the current research proposal seeks to test the central hypothesis that prenatal PAH exposure is associated with persistent irritability via effects on functional connectivity between control and reward circuits. This training and research program will support the candidate in becoming an independent investigator with expertise in how environmental (social and chemical) risk factors contribute to the manifestation of adolescent internalizing symptoms and anxiety/depressive disorders. RELEVANCE: Air pollution is an understudied, modifiable risk factor for an environmentally-associated phenotype of persistent childhood irritability. In the short term, this career development award will provide Dr. DeSerisy with critical training that will prepare her to successfully submit an R01 examining the contributions of prenatal PAH to adolescent anxiety and depression via persistent irritability in this cohort. Long term, results may inform public policy messaging and contribute to development of novel intervention and prevention tools.

NSF Awards · FY 2025 · 2025-09

With support from the Chemical Structure and Dynamics (CSD) and Chemical Theory, Models, and Computational Methods (CTMC) programs in the Division of Chemistry, Professors Lawrence Baker of Ohio State University, Xiaosong Li of University of Washington, Sharon Hammes-Schiffer of Princeton University, and Krupa Ramasesha of Sandia National Laboratory will organize a three-day workshop focused on ultrafast photochemistry and photocatalysis. The workshop will convene leading researchers across theory and experiment to address critical scientific challenges and explore opportunities for interdisciplinary collaboration in ultrafast photochemistry and photocatalysis. Recent advances in experimental techniques as well as new theoretical methods make this a fruitful area for collaborations with potential to advance fundamental understanding of key chemical transformations, resulting in more efficient and selective chemical processing, energy conversion, and storage. This workshop will provide a timely forum for discussing cutting-edge developments in experimental and theoretical approaches to ultrafast photochemistry and photocatalysis, with the goal to foster new collaborations and promote scientific and educational innovation across disciplines. Ultrafast pulses have become increasingly powerful tools for probing electronic and nuclear structural dynamics in chemical systems, from isolated molecules to nanoscale materials and interfaces to complex biological assemblies. Recent advances in both the development of and access to ultrafast light sources, especially at short wavelengths, have significantly enhanced the community’s ability to directly observe ultrafast electron and nuclear motion through a combination of spectroscopy, diffraction, and imaging experiments. These techniques now offer new insights into the time-resolved dynamics that govern photochemical and photocatalytic processes. While these experimental breakthroughs open new windows into fundamental chemical processes, they also present major theoretical and computational challenges. This workshop will address the need to integrate advances in ultrafast experimental techniques with state-of-the-art theoretical modeling by laying the groundwork for innovative collaborations between experiment and theory. The resulting workshop report will serve as a roadmap to the community for tackling open questions in excited-state electronic structure, core-level spectroscopies, and time-resolved photochemistry. 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.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This is the Data Coordinating Center’s grant proposal for the “Delaying the Onset of Nearsightedness (DONUT) Study – Data Coordinating Center”, a randomized clinical trial designed to compare the effectiveness 0.05% atropine and a placebo in delaying the onset of nearsightedness. We propose a multicenter (14 clinic centers) randomized clinical trial of 606 children (recruited over two years) ages 6 to 11 years who are determine to be at high risk of myopia onset, as measured by cycloplegic autorefraction and age. The aims of this clinical trial will test whether or not the onset of myopia is delayed in a group of children randomized to nightly drops in 0.05% atropine in both eyes, in comparison to children who receiving nightly placebo drops in both eyes. The second aim of this project will determine whether atropine is associated with slower axial elongation in children receiving nightly drops of atropine versus placebo. This Data Coordinating Center’s grant proposal provides the clinical centers, sample size and rationale, data management and analysis for this clinical trial. Accompanying documents include the Clinical Center Plan, Data Management and Handling, and the Statistical Analysis Plan attachments. There are also another application linked to the Data Coordinating Center Grant – the DONUT Study Chair’s grant application that provides the study rationale, design, and organization of this clinical trial.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY We propose the WINDSURFER trial to answer one of the signature questions of emergency care; “What is the best non-invasive respiratory support (NIRS) strategy for treating acute hypoxemic respiratory failure (AHRF) in the Emergency Department (ED)?” AHRF is the syndrome of impaired breathing resulting in low blood oxygen levels, most commonly from lung or other infections, acute decompensated heart failure (ADHF) and chronic obstructive pulmonary disease (COPD). AHRF is a major public health problem as evidenced by its seasonal and pandemic surges and the >100,000 associated deaths each year in the United States. Aggressive treatment of AHRF at its earliest stages in the Emergency Department (ED) is essential to prevent progression to death. Non-Invasive Respiratory Support (NIRS) is an important and widely used rescue treatment for AHRF that provides effective high-level breathing support without the pitfalls and consequences of mechanical ventilation. The two forms of NIRS are: 1) Non-Invasive Positive Pressure Ventilation (NIPPV), which includes continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP)], and 2) Heated High-Flow Nasal Oxygen (HFNO). NIPPV supports breathing by delivering high pressured oxygen through a tight-fitting face mask. In contrast, HFNO supports breathing by delivering high flows of heated and humidified oxygen through a specially designed nasal tube. The best NIRS strategy for AHRF is unknown. The optimal treatment for AHRF must be effective, safe, easy to deploy, comfortable for patients and effective across a spectrum of diseases and comorbidities. We propose a new clinical trial, WIN ratio analysis to Determine a strategy of non-invasive SUpport for Respiratory Failure in the EmeRgency Department (WINDSURFER), to determine the best initial NIRS strategy for patients presenting to the ED with AHRF. We will execute the trial using EDs selected from the NIH Strategies to Innovate Emergency Care Clinical Trials Network (SIREN). We will randomize adult ED patients (n=500) with AHRF to a treatment strategy of 12 hours of NIPPV or HFNO. The primary outcome is the hierarchical Major Adverse Pulmonary Events (MAPE): 1) hospital mortality, 2) ventilator-free days, and 3) NIRS hours. We will compare differences in MAPE between NIPPV and HFNO using the Win Ratio, a novel technique to assess differences in a hierarchical composite outcome. Our aims are: Aim I: Determine the effectiveness of ED NIRS strategies (NIPPV vs. HFNO) upon AHRF outcomes. We will test the hypothesis that HFNO is superior to NIPPV, as demonstrated by lower MAPE. Aim II: Evaluate the safety of ED NIRS strategies (NIPPV vs. HFNO) in AHRF. We will evaluate the risk differences between NIPPV and HFNO for the development or worsening of three specific safety outcomes: 1) pneumonia/ pneumonitis, 2) ARDS and 3) shock.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Rates of major depressive disorder (MDD) sharply increase in adolescence, particularly for girls, with approximately 30% of girls experiencing an episode of MDD by adulthood. Stress-reactive rumination (SRR), the tendency to engage in rumination following the experience of stress or negative events, has been identified as a specific mechanism of depression risk for adolescent girls that may be an important target for intervention. Yet, progress in translating this research to targeted prevention and intervention efforts is hindered by a lack of understanding of 1) the precise neural and behavioral mechanisms through which SRR eventuates in future youth depression risk, 2) how these processes unfold over time in real-world settings, 3) key factors that promote or mitigate altered SRR patterns and future depression in adolescent girls, and 4) how and when changes in SRR over development, versus a single time point, correspond to changes in depression during adolescence. Addressing these questions is pivotal for determining which adolescent females should be targeted with prevention or intervention efforts aimed at modifying SRR patterns and identifying optimal windows for intervention. The current R01 will employ a novel, multimodal, longitudinal study to test whether alterations in cognitive-affective brain networks (salience emotional, cognitive control, and default-mode networks) during stress-induced rumination predict future depression trajectories in adolescent girls (Aim 1). To increase the ecological validity and applicability of this work, we will also test if naturalistic (ecological momentary assessment, EMA) experiences of stress reactive rumination in response to day-to-day stressors predict increases in daily depressive symptoms (Aim 2). We will assess factors that protect against (i.e., family cohesion) or exacerbate (i.e., early life adversity) alterations in stress-reactive rumination development and subsequent depression to identify adolescent girls who could most benefit from targeted interventions (Aim 3). Finally, by adding three time points of neuroimaging, EMA, and depression assessments, we will build on prior work by studying trajectories of change (and predictive modeling) in rumination across naturalistic and brain levels (Aim 4). To achieve these aims, we will leverage our unique access to risk-enhanced youth in Columbus to recruit 210 youth females aged 10-14. At baseline, 12- and 24-months, youth will complete a reliable stress-induced rumination task during magnetic resonance imaging and resting-state scan to measure key cognitive-affective brain networks. Each imaging time pointed is time-locked to the 14-day EMA protocol to capture rumination and other coping strategy use following daily stressors. Family relationship quality and cohesion and child early life adversity exposure at individual and community-levels will be assessed at every time point, along with parent, youth, and clinician- rated assessments of child’s depressive symptoms and disorders. Findings from the project may lead to novel stress-reactive rumination prevention programs that could be delivered during early adolescence prior to the emergence of depression to break risk cycles more effectively.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The increased high-sugar and high-fat diet consumption directly contributes to the prevalence of obesity and metabolic disorders. The enteroendocrine cells (EECs) are critical chemosensory cells in the intestinal epithelium. Following food ingestion, the nutrients in the intestinal lumen are sensed by a subset of EECs. Recent research demonstrated that the EECs that express Cholecystokinin (CCK) possess basal membrane processes called neuropod to form synaptic connections with the vagal sensory nerve fiber. Through the CCK+EECs-vagal synaptic connection, the nutrient information in the intestinal lumen can be sensed and transmitted to the brain. The CCK+EEC-vagal circuitry plays important roles in regulating food preference and feeding behavior. However, the molecular mechanisms and the environmental factors that regulate the EEC-vagal synaptic connections remain entirely unknown. Moreover, our general understanding of the signaling molecules that drive the vagal innervation in the intestine and the mechanisms that regulate the intestinal vagal network remains extremely limited. As a result, our ability to manipulate intestinal vagal signaling and target gut-brain nutrient sensing to treat diseases associated with feeding dysfunction and metabolic disorders is handicapped. The proposed study will use novel genetic tools in zebrafish models and in vivo imaging to directly visualize the dynamic EEC-vagal synaptic communication in live animals. Our preliminary data demonstrate that EECs are important for remodeling the intestinal vagal network and CCK+EECs express Brain-derived neurotrophic factor (Bdnf). This proposal will test the central hypothesis that feeding and nutrients dynamically regulate CCK+EECs Bdnf signaling to remodel CCK+EEC-vagal synaptic connections and the intestinal vagal network. The first aim will use genetic tools and CRISPR screening to determine the environmental factors and molecular mechanisms that regulate Bdnf expression in CCK+EECs. The second aim will use a novel genetic approach to directly visualize in vivo EEC-vagal synaptic connections to determine the role of Bdnf signaling in CCK+EECs in regulating the EEC-vagal synaptic connections and the intestinal vagal network. Accomplishing this proposal is expected to reveal the first molecular mechanism and cellular signaling that drive the formation of the EEC-vagal synaptic connection. It will reveal novel mechanisms that modulate the intestinal vagal network, enhance EEC-vagal signaling transmission, and promote gut- brain nutrient sensing. Selectively manipulating the EEC Bdnf signaling will offer new opportunities to treat diseases that are associated with vagal disorders and gut-brain nutrient sensing dysfunction.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The current topic involves the deleterious effect of noise on speech understanding. This has been a topic of considerable interest for many decades, motivated in part by the fact that difficulty understanding speech when background noise is present represents the primary auditory complaint of individuals with hearing loss. We argue here that a critical barrier to progress involves an incomplete understanding of the basic effect. A long- standing assumption, which is deeply ingrained in the field, is that the impact of noise on speech intelligibility is the same in all frequency regions. Said differently, adding noise at a given signal-to-noise ratio (SNR) is assumed to be equally detrimental to a band of speech in the low frequencies as it is to a band of speech in the middle or high frequencies. There exist many examples of this assumption, and it has shaped our thinking for many decades. However, in sharp contrast to this assumption, we recently revealed that the susceptibility of speech to noise is not at all the same across frequencies. Instead, the SNR required to impact speech equally varies across the spectrum by as much as 13 dB (Yoho et al., 2018). The proposed study will comprehensively establish this concept of “noise susceptibility.” In Aim 1, we will confirm, refine, and extend the initial finding. Noise at various levels will be added to individual speech bands to modulate their contribution to intelligibility between two well-defined boundaries. The overall amount of noise required to affect the contribution of a band, together with the rate of change, will determine its noise susceptibility. This will be done for each of 20 ANSI critical bands, resulting in detailed noise-susceptibility functions across frequencies. In Aim 2, we will expand our understanding of noise susceptibility by using maskers that impact speech via different mechanisms (Stone et al., 2011, 2012; Stone & Moore, 2014). Notionally steady noise operates primarily via modulation masking. Pure-tone maskers allow an examination of energetic masking. Noises that operate via modulation masking and have additional slow acoustic modulations introduce masking release. Each of these maskers will be used to create noise-susceptibility functions representing differential susceptibility across the speech spectrum, and the shapes of these functions will be compared. The information gained will reveal the degree to which maskers that operate via different mechanisms impact speech in different frequencies. This work will further our fundamental understanding of speech perception in noisy environments by advancing the noise-susceptibility concept and clarifying the various mechanisms of speech masking. The future implications of this knowledge are many. They include incorporation into a refined SII (ANSI, R2024) and the creation of noise-reduction systems tailored to focus on frequency regions where speech is least robust to noise, thus improving speech understanding for the 30 million Americans with hearing loss (NIDCD, 2024). Overall, the increased fundamental understanding, the rectification of decades of incorrect assumption, and the many implications have the potential to be transformative.

NIH Research Projects · FY 2025 · 2025-09

Emergency departments (EDs) provide ~140 million encounters annually for all populations (i.e., varying demographics, injuries, comorbidities) and serve as a primary safety net in U.S. healthcare infrastructure for individuals often not encountered elsewhere. Moreover, over 80% of these patients are experiencing pain with variable causes, perceptions, and environmental influences challenging our understanding to optimize diagnosis, prognostication, and treatment. This proposal seeks to leverage the ED setting to comprehensively characterize the full range of interindividual differences in acute pain phenotypes, optimal treatment, and trajectories of pain within a biopsychosocial and health services framework. We aim to: 1) Characterize clinically informed pain phenotypes with a data-driven modeling approach, 2) Identify optimal pain treatment strategies using individualized treatment regimen (ITR) estimation method, and 3) Develop predictive models of pain trajectories and predict transition from acute to chronic pain. We will collect the necessary data for robust and comprehensive data-driven modeling in a prospective observational study of (n=2,400) ED patients seeking care for acute pain. In addition to NIH HEAL core domains, we will collect self-reported data, health records, digital physiologic markers, and biologic samples to measure: (i) AHRQ social determinants of health, (ii) character, severity, timing of pain, (iii) perceptions, resiliency, and beliefs, (iv) co-morbidities (medical and mental health), (v) physical function and sleep interruptions, (vi) digital physiologic data, (vii) measures of pain sensitivity (e.g. Von Frey, thermal thresholds), (viii) healthcare utilization, (ix) treatment access/effectiveness, and (x) genome-wide single nucleotide polymorphisms. Our comprehensive modeling approach will combine advanced and cutting-edge methods, informed by an expert panel including persons with lived experience of chronic pain, community stakeholders, and clinicians allowing the development of clinically interpretable predictive models. This innovative and high-impact investigation will provide the missing link in our understanding of pain by embracing the required breadth and complexity. Our remarkably interdisciplinary team is well-positioned for this significant challenge. We will capitalize on (i) ED care for all types of pain occurring in persons with comorbidities and (ii) our proven capacity for a longitudinal study of often challenging populations in episodic care environments without ongoing provider relationships. Our inclusion of psychosocial, cognitive, biologic, and health services measurement is an enormous and necessary advance. The quintessential contribution of this research will be models appropriate to the challenge of pain heterogeneity, health disparities, and pain itself. Without this foundation, we cannot hope to identify intervention targets and develop novel interventions sufficient to fundamentally transform current patterns in pain-related health outcomes and disparities.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The central theme of this proposal is to develop technologies that will enable the extraction of chemical infor- mation from organoids. Organoids are cell cultures that are grown directly from human or animal tissues and can be generated from either healthy or diseased specimens. They are disease-agnostic and have been gen- erated from almost every organ in the human body, making them a valuable resource to study fundamental bi- ology, structure, and reactivity. Because they can be grown directly from human patients, there is considerable buzz surrounding them for their applications in disease prognosis and evaluating transplantation success. They also hold great promise in the arena of drug development, especially given new changes in legislation. In late 2022, the legislation governing drug testing in the United States was altered with the FDA Modernization Act 2.0. Previously, all new therapeutics had to be tested with an animal model prior to reaching the American pub- lic. However, with these laws in place, the use of organoids to evaluate new drugs is not just allowed but en- couraged. Despite these advances, the analytical strategies used to analyze organoids are lacking, especially protein analysis. In most organoid studies to date, protein analysis is completed by immunohistochemistry or cytokine arrays. While these methods offer information on a specific, pre-selected short list of proteins, they do not allow any novel protein discoveries. Especially in the arena of drug testing, where evaluation of off-target effects is critical, a discovery-based method that allows broad sampling of the proteome is needed. In this pro- posal, we outline the development of a suite of mass spectrometry approaches that will enable exploration of the organoid proteome, in a cell specific manner. Using magnetic sorting to separate the different cellular spe- cies of interest, followed by global mass spectrometry profiling, we will parse the relative contributions to the proteome for the different constituent cell types that encompass the multicellular organoid. The proteomic changes will then be validated by means of imaging mass spectrometry analysis on the organoid sections. The research to be conducted will be with lung organoids, based on a current successful collaboration between our laboratory and a group of pulmonologists, however the methods we develop will be applicable to organoids grown from any organ in the human body, thus impacting a wide range of human diseases. As we develop our methods, we will explore proteins involved in senescence, a fundamental cellular process characterized by a gradual deterioration of the functional characteristics in a mammalian cell. Senescence occurs throughout the human body yet the protein markers commonly used to characterize it lack specificity. With the combination of relevant lung organoid models and global discovery proteomics, we will elucidate alternative and better mark- ers for senescence in the human lung. Again, while our methods will be developed with lung cells, these ap- proaches will be applicable to organoids grown from any organ. With these advances, organoids will be poised to expand on their clinical promise in the areas of disease prognosis, transplantation, and drug screening.

NIH Research Projects · FY 2025 · 2025-09

Mitochondria have been shown to play a central role in cardiac contractility and the process is tightly regulated by electron transport chain (ETC) efficiency. Mitochondrial functions including ATP generation and ROS production by ETC are tightly coupled with ionic homeostasis and coordinated regulated signaling between nuclear-cytoplasmic and mitochondrial components. Tremendous progress has been made in deciphering the mechanistic role of mitochondria in protecting the heart from cardiac hypertrophy in animal models. Yet, it remains a substantial challenge to dissect the critical contribution of mitochondria to cardiac hypertrophy and to establish a rigorous relationship between energetics, signaling pathways, and specific aspects of cellular and organ hypertrophy. The potassium channel sensitive to voltage and calcium (BK) present in cardiomyocytes has been shown as a splice variant of plasma membrane BK and is exclusively present in mitochondrial membranes (referred to as mitoBK). Though activation of cardiac mitoBK is known to play a role in cardioprotection possibly by regulation of mitochondrial function, the precise mechanism of mitoBK in regulating cardiac function and protecting the heart from pathological hypertrophy (or cardioprotection from IR injury) is not yet established. We will now test the hypotheses that: cardiac mitoBK protects against pathological cardiac hypertrophy by regulating mitochondrial biogenesis and function via modulating the levels of UCPs, through signaling pathways governed by PGC-1α, and FOXO3a. Our published, as well as preliminary data, show that: 1) mitoBKCa is encoded by Kcnma1 gene, and a DEC splice variant governs its mitochondrial localization; 2) absence of mitoBK causes cardiac hypertrophy, fibrosis, and cardiac dysfunction; 3) absence of mitoBK augment cardiac hypertrophy after pressure overload insult whereas genetic activation protects the heart, 4) expression of mitoBK is vital for handing mitochondrial calcium and ROS levels after pressure overload, 5) absence of mitoBK results in changes in expression of UCPs, PGC-1α, and FOXO3a. Our preliminary data support our hypothesis that cardiac mitoBK, exclusively present in the mitochondria of adult cardiomyocytes, plays a cardioprotective role in cardiac hypertrophy. This will be tested by an array of multidisciplinary collaborative approaches using mouse genetics. In that regard, we will pursue the following specific aims: 1) To determine the role and mechanisms of mitoBK channel mediated changes in mitochondrial function in left ventricular hypertrophy; and 2) To elucidate mechanisms whereby retrograde signaling influences mitoBK activity, and expression of transcriptional coactivators and UCPs in left ventricular hypertrophy. This research program will be the first proposal that will determine the precise signaling mechanism of how cardiac mitoBK channels directly play a role in mitochondrial physiology, and cardiac function, and protect the heart from pathological cardiac hypertrophy.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Adverse cardiovascular health (CVH) is the leading cause of pregnancy-related deaths in the US, which have increased 140% over the past three decades. Adverse CVH disproportionately affects pregnant individuals who experience adverse social determinants of health (SDOH) and directly contributes to marked disparities in maternal CVH. SDOH should be understood as a multi-dimensional construct to be measured and intervened upon at multiple-levels, including both individual- and neighborhood-level SDOH (iSDOH, nSDOH). An individual’s lived experience, which are shaped by experiences of both iSDOH and nSDOH, directly impacts CVH across the lifespan, including during pregnancy and the postpartum. Yet, during this important moment in a woman’s life, the relationship of SDOH factors with adverse CVH, including clinical factors, adverse pregnancy outcmes (APOs), and ultimately, cardiovascular disease (CVD) remains uncertain. In addition, nSDOH remain poorly characterized and understood during pregnancy and the postpartum. Healthy People 2030, professional recommendations, and NHLBI’s Strategic Vision Implementation Plan emphasize that effective population-level structural interventions and policies to improve CVH requires a mechanistic, holistic and integrated understanding of SDOH factors. Efforts to quantify the influence of SDOH factors on CVH have largely failed because the causal pathways are numerous, interconnected, and complex. A promising approach to test the inter-relationships of multiple SDOH factors over time is a polysocial risk score. We will harness the prospective, nuMoM2b nulliparous pregnancy cohort (nuMoM2b) and the ongoing postpartum follow-up nuMoM2b Heart Health Study (HHS). This contemporary, generalizable, and deeply phenotyped population includes >10,000 individuals during their first birth experience from across eight US centers. We will employ contemporary theoretical frameworks, machine learning, advanced Bayesian methods, and participant- engaged data walks to construct concepts, identify relationships, and shape future policy and multi-level interventions addressing SDOH and maternal CVH. Our premise in MomHeart is that maternal CVH is spatially patterned by multiple, intersecting socially-mediated factors in the peripartum period. We will accomplish three complementary specific aims: 1: Determine associations of individual iSDOH and nSDOH with maternal CVH (clinical factors, APOs, composite CVH, and predicted CVD risk), cross-sectionally and longitudinally; 2: Examine the intersectionality of iSDOH and nSDOH through a polysocial risk score and examine the associations between a polysocial risk score and maternal CVH; and 3: Conduct qualitative interviews with active nuMoM2b-HHS participants with lived experience to elucidate perspectives on how SDOH patterns discerned have had relevance to their own CVH and could serve as intervention points to improve maternal CVH. MomHeart will shape the future of precise and targeted multi-level interventions and public health policies to enhance the CVH of the highest risk pregnant and postpartum indivduals.

NIH Research Projects · FY 2025 · 2025-09

KRAS is one of the most commonly mutated proteins in cancer and efforts to directly inhibit its function have been ongoing for decades. The most successful of these efforts has been the development of covalent allele specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumor growth in patients. Whether inactive state selective inhibition can be employed to therapeutically target non-G12C KRAS mutants remains under investigation. We have recently discovered and characterized a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS, while sparing NRAS and HRAS. Our study suggests that most KRAS oncoproteins cycle between an active and inactive state in cancer cells and the inhibitor can prevent activation of wild-type and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, Q61H, K117N and A146V/T. Based on preliminary results and through comprehensive genetic, biochemical, transcriptomic and proteomic approaches, I will now study the regulation of different KRAS oncoproteins in cancer cells and identify optimal therapeutic applications. In this proposal I will aim to identify mutant specific features (aim 1), regulators (aim 2), and combination therapy (aim 3) throughout KRAS mutant cell lines and mouse models using the pan-KRAS inhibitor (KRASi) described above. The impact of the proposed work here will provide new insight into molecular and biochemical properties of KRAS oncoproteins in cancer. The training component described in the proposed work includes activities to facilitate my transition to an independent principal investigator position. During the K22 phase, I will attend courses, gain hands on experience in order to learn new techniques and attend meetings to expand my network for future collaborations. This award will provide me with the necessary resources and expertise to ensure the successful completion of the training phase of the grant, so that I can transition to a productive career as an independent and well-rounded principal investigator.

NSF Awards · FY 2025 · 2025-09

How proteins interact inside plant cells plays a vital role in how plants grow, adapt, and defend themselves against pests and environmental stresses. However, current tools to study these interactions often rely on non-native systems or invasive methods that can disrupt natural cellular processes. This project will develop a novel, non-invasive protein delivery system to deliver proteins directly into native plant tissues. The new system uses a small, engineered protein called MTD4, which can carry functional proteins into plant cells without disruptive delivery systems and much more efficiently than previous methods. This innovation enables researchers to observe the activity of proteins in real time within live, physiologically intact plant cells, offering a clearer picture of how plant responses are regulated. The approach is fast, flexible, and applicable to a variety of plant species, making it a powerful tool for functional genomics. Development of the system will generate proteomics data from protein-protein interactions that can be used for further functional analysis by the plant community. The project involves strong training and outreach components, providing hands-on research opportunities for graduate students, postdocs, and undergraduates. Through a partnership with Ohio’s Farm Science Review, students will engage with farmers and the public to communicate scientific discoveries and real-world agricultural challenges through storytelling and creative media. This project will enhance our understanding of plant genomes, foster interdisciplinary education, and support the development of resilient, high-performing crops for a sustainable future. This project aims to develop an intracellular protein delivery (ICPD) system to enable study of proteins delivered into plant cells in a physiologically relevant context, by leveraging a highly active membrane translocation domain, MTD4. Current delivery systems, including heterologous expression systems, protoplast transfection, and agroinfiltration are limited by the lack of cellular context, slow protein expression, and/or unintended stress responses. Preliminary studies demonstrate that MTD4 is capable of rapidly delivering a variety of soluble proteins directly into the cytosol of plant cells, with minimal damage to the plant. This project aims to: (1) optimize the ICPD system in tomato and Arabidopsis, and (2) develop ICPD for delivering cargo proteins into various subcellular organelles. This system delivers proteins into plant cells via foliar spray, enabling nuanced analyses of protein function and interactions in real time. By preserving cellular integrity and context, ICPD represents a significant advancement in functional genomics tools for plants. Beyond basic discovery, ICPD has biotechnology potential in high-throughput screening applications and synthetic biology approaches. The project provides robust training and outreach activities designed to foster the next generation of plant scientists and communicators strengthening capacity in plant biology and agricultural biotechnology. Project data resources will be accessible through long-term public repositories. 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.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY (See instructions): Cell growth and division are the essential processes for tissue homeostasis, regeneration, and cancer development. Therefore, the study of cell growth regulation is important for understanding impaired tissue regeneration and tumorigenesis. Cell growth and cell division are coordinated via mutual regulation, and these two processes together determine a fundamental cellular property, the cell size. The molecular mechanisms underlying the linkages between these processes are largely unknown. Cell growth can trigger cell division by diluting the cell cycle inhibitor RB, which contributes to the maintenance of cell size homeostasis. The RB dilution mechanism relies on the cell cycle-dependent RB concentration dynamics, but the underlying mechanism is still unclear. On the other hand, cell cycle and cell size can feed back to regulate cell growth rate, of which the mechanisms are yet unknown. I found that the protein synthesis efficiency, a major determinant of cell growth efficiency, increases at the G1/S transition and decreases as cells grow larger within each cell cycle phase, suggesting that the global protein synthesis rate is actively regulated to facilitate cell cycle progression and cell size control. Here, in this proposal, I aim to address these gaps in our knowledge by determining the molecular mechanisms regulating RB concentration and global protein synthesis during cell cycle progression and cell growth. During the K99 phase, I’ve determined the molecular mechanisms underlying the RB concentration regulation during cell cycle progression (Aim1), which further revealed the molecular basis of how cell growth triggers cell division. During the R00 phase, I will continue to study how global protein synthesis is regulated during cell cycle progression (Aim2), which will help us understand how cell cycle regulates cell growth. These two aims link cell growth with cell division from the perspective of protein synthesis regulation. Then, the study on how protein synthesis is regulated during cell growth (Aim3), which will be pursued during R00 phase, explores the mechanism of how cell size feeds back to regulate growth rate. Thus, the three aims together set up a foundation towards a deeper understanding of the principles governing cell growth and proliferation. The completion of above aims will deepen our understanding of the fundamental molecular mechanisms regulating protein synthesis and cell growth rate, and therefore have broad impacts on cell and developmental biology. Moreover, this work will enhance our understanding of tissue regeneration deficiencies and tumorigenesis.

NIH Research Projects · FY 2025 · 2025-09

Health disparities are preventable and identifying their social determinants and underlying mechanisms is of high scientific priority. A 2020 National Academies of Sciences report articulated a clear national agenda to target health disparities among the sexual minority (SM) population, and there is a renewed focus on research to address disparities among racial and ethnic minority individuals. Critically, data on biological mechanisms linking stress and health in the SM population are limited. We will assess inflammation via serum interleukin(IL)-6 and C-reactive protein (CRP). Low-grade, chronic inflammation is implicated in age-associated frailty, morbidity, mortality, and accelerated epigenetic aging.36 Epigenetic age, is a highly novel and robust predictor of multiple diseases, longevity, and all-cause mortality. Examining epigenetic clocks through DNA methylation offers a cutting-edge approach allowing us to answer critical questions: Does SM stress accelerate aging? Can stigma and discrimination propel molecular aging and shorten health span (the length of time that a person is healthy—not just alive)? Capitalizing on a time-sensitive, unparalleled opportunity to add biological data collection to the National Couples’ Health and Time Study (NCHAT) to create additional data for the NCHAT Stress Biology Study (NCHAT-BIO), we aim to fill these empirical gaps. Funded by NIH, NCHAT is the only longitudinal, probability, population-representative study (N = 3,642, ages 22-67, 50% women) with representation of heterosexual (55%), sexual minority (45%), non-Hispanic white (62%), and racial and ethnic minority (38%) coupled adults with comprehensive psychosocial measurement. This project advances innovative health research by combining survey data on stressor exposures, psychological health, and health behaviors with biological data from an estimated 2000 of NCHAT’s respondents. Aim 1: Delineate differences in epigenetic aging and inflammation by sexual orientation and test interaction effects of sex and race/ethnicity. Aim 2: Determine effects of sexual minority stressors on epigenetic aging and inflammation. Aim 3: Identify modifiable factors linking sexual orientation and sexual minority stressors with epigenetic aging and inflammation. Sexual minorities face significantly greater risk for chronic health conditions than heterosexuals. The biological underpinnings of these group differences have been minimally studied representing an unacceptable gap in knowledge. This study offers the remarkable opportunity to examine epigenetic aging and inflammation in a large, US-representative sexual minority and heterosexual population, permitting crucial tests of mechanisms linking stress and health, and interaction effects of race/ethnicity and sex. This research promises to uncover modifiable treatment targets to address health disparities. The resultant assays will be publicly available to other researchers via ICPSR offering an unrivaled resource for future researchers. By leveraging NCHAT to create NCHAT-BIO, this is a singular and time urgent opportunity.