University Of Iowa

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Significance: Prematurity a major health problem in the United States, with more than 385,000 babies born preterm annually. The economic cost is more than $50 billion, mostly in extremely low birth weight infants (ELBW, born<1000g). Patent ductus arteriosus (PDA) is the most common cardiovascular problem and requires interventional closure in 16% of cases. Intervention is complicated by Post-Ligation Cardiac Syndrome (PLCS), characterized by low or high blood pressure and respiratory instability, with highest incidence in the most immature patients. Both PDA surgery and PLCS are independently associated with increased risk of adverse respiratory outcomes and neuro-developmental disabilities. Of surviving ELBW infants after PDA closure, 50% had neurodevelopmental impairment including severe handicaps. Postprocedural instability is decreased by early milrinone use, a vasodilator drug which enhances heart function. Avoiding postprocedural instability and establishing the safety of milrinone are considered important outcomes by parents. Investigators and Prior Work: Prospective observational mechanistic data demonstrates that PLCS relates to inability of the immature myocardium to tolerate the change in left ventricular loading conditions. Preliminary data demonstrates the efficacy of milrinone in reducing the incidence of PLCS through optimizing heart function. The Clinical Coordinating Center MPI Dr. Patrick McNamara, a world leading hemodynamics scientist, conducted the original mechanistic studies which characterized the biological mechanisms of PLCS and the pharmacology of milrinone. Dr Edward Bell (MPI) has an extensive record in leading multicenter clinical trials and the Data Coordinating Center (DCC) PI Dr. Abhik Das has led several NHLBI funded trials. Innovation: In most centers PLCS is recognized late, when hypotension is severe, and prompts use of vasopressor drugs which impair heart function. There are no prior randomized clinical trials of milrinone after PDA closure; therefore, neither treatment efficacy nor long-term safety is known. We propose a randomized controlled trial (RCT) to evaluate the immediate benefits of milrinone in decreasing the rate of PLCS and 7-day mortality. The need to assess long-term outcomes of RCTs is compelling to ensure treatment safety. Approach: We will perform a RCT in preterm infants born less than 28 weeks’ gestation asking: “Does routine use of intravenous milrinone lower the risk of PLCS or mortality within 7 days of intervention and is treatment safe?” The question is relevant to the mission of NHLBI and aligns with parental values to minimize postprocedural risk. In addition, it represents a paradigm shift in Neonatology to conduct clinical trials of treatments that offer biologic plausibility in illnesses that have been mechanistically characterized. Environment: We have partnered with the NICHD Neonatal Research Network (NRN), which includes 15 clinical centers, and have added 4 additional sites to maximize enrollment capabilities. We believe this trial is both feasible and achievable based on the prior track record of NRN in completing meaningful clinical trials.

NIH Research Projects · FY 2025 · 2024-07

OVERALL – PROJECT SUMMARY/ABSTRACT Vision and Mission: The vision of the Heartland Center for Occupational Health and Safety (the Heartland Center) is to be the leading educational and outreach resource for occupational safety and health in the states of Iowa, Kansas, Missouri and Nebraska (Region VII). The Center’s mission is to reduce injuries, illnesses, and fatalities of workers by expanding and strengthening the occupational health and safety workforce with well- trained and well-informed professionals. Objective: The academic training provided by the Heartland Center will increase the number of highly knowledgeable and experienced occupational health and safety (OHS) professionals in Federal Region VII (Iowa, Nebraska, Kansas and Missouri). The Center’s outreach and continuing education programs will enhance the capabilities of occupational health and safety professionals to reduce the high rates of occupational disease and injury in this region. Rationale: The major rationale for the Heartland Center is to satisfy the need for OHS professionals in this Region, provide practical information for the professional development of OHS professionals in this Region, and serve as a conduit of OHS-related information to this Region. The Center will consist of 5 graduate level training programs, including industrial hygiene, occupational safety, ergonomics, agricultural safety and health, and occupational injury prevention. The Center will also contain active continuing education and outreach program designed to reach thousands of OHS professionals in the Region using traditional and innovative distance-education technology and information dissemination techniques. The Center is structured to maximize its mission with a central administration guided by a strategic plan and input by an active internal and external advisory board. A strong evaluation plan is used to monitor all aspects of Center effectiveness. A comprehensive diversity recruitment plan enhances the enrollment of students from underrepresented populations. The project team is committed to diversity, equity, inclusion and accessibility in all aspects of the Heartland Center. Programs: This proposal supports a request for continued funding of the Heartland Center during the period 2024 - 2029. The minimum annual number of trainees in each program area are the following: Industrial Hygiene - 5 master's, 1 doctoral); Occupational Safety - 3 master's, 1 doctoral; Ergonomics – 2 master’s, 1 doctoral; Agricultural Safety and Health - 2 master's, 2 doctoral; Occupational Injury Prevention - 1 master's, 2 doctoral; Continuing Education (CE) – 1600 participants.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract The elevated risk of language and reading disorders (as high as 60%) among children with isolated cleft of the lip and/or palate (iCL/P) is a significant clinical concern, substantiated by research since the 1980’s. These disabilities, while not in the range of intellectual dysfunction, do result in academic achievement problems and lower rates of college attendance. Neuroimaging work in children, adolescents, and young adults with iCL/P has identified an association between these deficits and patterns of aberrant neural development and disrupted activation during reading tasks. The critical next step in this line of work is to determine the etiology of these language deficits and the associated neural patterns. Current hypotheses postulate that deficits may be due to events very early in life, including 1) repeated exposure to anesthesia, 2) airway obstruction/reduced oxygenation, and 3) genetic/biological factors disrupting neural migration and brain development. To fully evaluate these theories, imaging work needs to be done on infants before and after their first surgery, with information on oxygenation, pre-speech functioning, and neural development obtained in tandem. The lack of such research is a crucial gap in the field, precluding essential information needed to inform clinical decisions that may improve these outcomes (e.g., treatment protocols and appropriate interventions). In the proposed study, infants with iCL/P and unaffected controls will undergo assessment at 2, 6-8, and 14-16 months of age; providing pre- and post-surgery measures for infants with iCL/P. At each time point, innovative techniques of brain imaging (through MRI and fNIRS) and multi-modal assessment of speech/language (vocal recordings and clinical ratings) will be combined with continuous overnight pulse oximetry and systematic and structured medical chart review (for information on anesthesia exposure, clinically mandated sleep studies, medical interventions, and audiology assessments). Through an R56 (NIDCR), the PI and research team have demonstrated feasibility of this protocol with baseline data on 16 participants to date. Initial data reflects patterns of immature pre-speech development, disrupted cortical growth and activation, and more desaturation events for those with iCL/P prior to exposure to anesthesia. The current project aims to: 1) Use baseline data to assess the effects of cleft presence and overnight desaturation events on brain structure/function and pre-speech/language measures before exposure to anesthesia; 2) Use data from all timepoints to assess the longitudinal effects of desaturation events and exposure to anesthesia on neural and language outcomes for patients with and without iCL/P; and 3) Evaluate the relationship between measures of neural structure/function and language outcomes. The longitudinal approach and novel measures of pre-speech and neural functioning will significantly contribute to the understanding of development in infants with iCL/P and the impact of exposure to anesthesia and reduced oxygenation.

NSF Awards · FY 2024 · 2024-07

This EAGER IMPRESS-U project is jointly supported by NSF, US National Academy of Sciences, Office of Naval Research Global (DoD), and National Science Centre of Poland. The research will be conducted in collaborative partnership that unites the University of Iowa (US), Jagiellonian University (Poland), Kharkiv Institute of Physics and Technology (Ukraine), Karazin Kharkiv National University (Ukraine), Kharkiv Institute of Physics and Technology (Ukraine), and Kyushu Institute of Technology (Japan). The US portion of this EAGER IMPRESS-U project is co-funded by NSF Office of International Science and Engineering and MPS/PHY. A precise understanding of how neutrinos interact with nuclei provides a sensitive tool to investigate physics beyond the standard model. The neutrino-nuclear system is described by a Hamiltonian that includes interactions involving both nucleons and neutrinos. For neutrino energies near or above a billion electron volts the structure of this Hamiltonian is constrained by special relativity. The publication record of the PI and collaborators from Poland and Ukraine includes relativistic calculations of electrons and neutrinos scattering off of light nuclei. The PI and collaborators are investigating the structure of the Hamiltonian for a neutrino interacting with a Deuteron (the simplest nucleus). The least understood part of this Hamiltonian is an interaction that simultaneously involves the neutrino and both nucleons, which is expressed in terms of a ”two-nucleon current”. The goal of this collaboration is to determine a two-nucleon current that is consistent with the nuclear Hamiltonian. The collaboration supports graduate students in Poland and Ukraine and a post doc in neutrino physics. It sustains the physics infrastructure in Ukraine at this very challenging time. The scientific goal of this project is to construct a two-nucleon-neutrino current to use in relativistic neutrino-nucleus scattering calculations. The current is constructed using a transformation, advocated by the Ukrainian members of the collaboration, that transforms the Hamiltonian of a quantum field theory of nucleons and neutrinos to a Hamiltonian for a system of interacting stable particles. The same transformation is used to compute the corresponding two-nucleon electromagnetic current. A consistent model must provide a precise understanding of both electron and neutrino scattering from Deuterons. Both two-body currents have a similar structure but there is more data to constrain the electromagnetic current. The outcome of this project are comparisons of neutrino and electron – Deuteron scattering calculations to experiment, the determination of the contribution of the two-body currents to different scattering observables, and predictions of neutrino and electron scattering observables. While the calculation are for electron and neutrino-Deuteron scattering, both two-body currents appear in Hamiltonians for larger nuclei . This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-07

The skin is the largest organ in the body and the skin barrier – provided by the epidermis – is critical for life of all vertebrates. Physically, the skin protects from external threats including infectious agents and prevents from excessive loss of water from the body. This barrier function is first provided during embryonic development by a transient protective layer called the periderm. Although the genesis and loss of the periderm are the first and last steps in the development of the epidermis, the precise role of this transient embryonic layer remain mysterious. To improve the dissemination of knowledge about embryology and epidermal barrier, there is a need to understand how the periderm is formed, what it does, and a need to teach about it in the classroom. This project will use advanced microscopy to get detailed information about the structure of the periderm. This study will engage scientific illustrators to depict the genesis and loss of the periderm in a public-accessible manner and promote its inclusion in textbooks. It will also involve high school students in observing developing skin under the microscope and teach them about the periderm. Students will sketch and annotate specimens seen under the microscope and create an artistic rendering of the same specimen, both of which will be exhibited for public viewing. The work train students from high school through graduate levels in original scientific research. To understand how the periderm contributes to epidermal fate and function, this project will utilize a mouse model system, the Irf6-deficient embryo. Interferon Regulatory Factor 6 (IRF6) has long been described as a master regulator of terminal epidermal differentiation. While analyzing Irf6-deficient embryos, it was observed the presence of adhesion-associated defects in the formation of the palate and the limbs, as well as differentiation-associated defects in the morphogenesis of epithelial cells in the epidermis (i.e., keratinocytes). These mutant embryos also exhibited significant thickening of the embryonic epidermis, with aberrant periderm differentiation and striking expansion of the suprabasal (i.e., spinous) compartment and lack of the uppermost epidermal layers (granular and cornified). These defects are associated with taut skin and a leaky epidermis, features that are incompatible with life. Together these data support the central hypothesis that peridermal cells are required for terminal differentiation of the epidermis, and that their development and fate are regulated by the transcription factor IRF6. The proposed study will test this hypothesis, utilizing a combination of classic ultrastructural microscopy, state-of-the art microscopy, quantitative image analysis, murine genetics (using specific alleles), and systematic experimental approaches. 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 · 2024-07

Project Summary/Abstract Polychlorinated biphenyls (PCBs) are a group of environmental toxins that has been linked to an increased risk of heart disease, stroke, and cancer, as well as the development of metabolic syndromes such as obesity, hyperlipidemia, and type II diabetes. Metabolic diseases are characterized by both systemic and local inflammation with adipose tissue, the primary site of PCB accumulation. Adipose tissue is comprised of many cell types including adipocytes, adipose mesenchymal stem cells (MSCs), endothelial cells, and immune cells such as macrophages. Adipose tissue macrophages (ATMs) play an integral role in regulating the inflammatory state of adipose tissue and influencing adipocyte function. During the pathological expansion of adipose tissue, adipocytes become inflamed beginning a cascade of immune cell activation starting with ATMs. The changing adipocyte secretion profile polarizes the macrophages from an anti-inflammatory phenotype toward an inflammatory phenotype and increases the infiltration of macrophage precursors into adipose tissue. Furthermore, these inflammatory ATMs communicate with local adipocytes through the release of soluble factors causing additional metabolic disruption and lipid accumulation in adipocytes. Despite the essential role of ATMs in the regulation of adipocyte function and the known accumulation of PCBs in adipose tissue, little is known about how PCBs affect adipose through ATMs. We have previously shown that PCB-exposed adipocytes have decreased adiponectin and increased IL-8 secretion, two cytokines implicated in macrophage phenotype switching. Additionally, we have shown that macrophages exposed to PCBs are polarized toward a more inflammatory phenotype. The objective of this proposed research is to determine how PCBs alter adipocyte- macrophage crosstalk to influence the development of endocrine and metabolic disruption. We hypothesize that adipocyte-macrophage communication will be altered by PCB exposure resulting in functional changes for both cell types. Our approach to testing this hypothesis is divided into two aims. In Aim 1, we will assess how PCB- exposed adipocytes affect macrophage recruitment and polarization. In Aim 2, we will investigate how PCB- exposed macrophages affect adipocyte phenotype and adipogenesis. Through the completion of these aims, we will uncover the systems-level mechanisms by which PCBs contribute to adipose dysfunction and inflammation through the disruption of adipocyte-macrophage crosstalk. More broadly, this fellowship will help me achieve my goals of gaining experience in medicine, toxicology, bioengineering, and environmental chemistry to prepare for a future career in treating and researching diseases impacted by endocrine-disrupting chemicals.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY Significance: Prematurity a major health problem in the United States, with more than 385,000 babies born preterm annually. The economic cost is more than $50 billion, mostly in extremely low birth weight infants (ELBW, born<1000g). Patent ductus arteriosus (PDA) is the most common cardiovascular problem and requires interventional closure in 16% of cases. Intervention is complicated by Post-Ligation Cardiac Syndrome (PLCS), characterized by low or high blood pressure and respiratory instability, with highest incidence in the most immature patients. Both PDA surgery and PLCS are independently associated with increased risk of adverse respiratory outcomes and neuro-developmental disabilities. Of surviving ELBW infants after PDA closure, 50% had neurodevelopmental impairment including severe handicaps. Postprocedural instability is decreased by early milrinone use, a vasodilator drug which enhances heart function. Avoiding postprocedural instability and establishing the safety of milrinone are considered important outcomes by parents. Investigators and Prior Work: Prospective observational mechanistic data demonstrates that PLCS relates to inability of the immature myocardium to tolerate the change in left ventricular loading conditions. Preliminary data demonstrates the efficacy of milrinone in reducing the incidence of PLCS through optimizing heart function. The Clinical Coordinating Center MPI Dr. Patrick McNamara, a world leading hemodynamics scientist, conducted the original mechanistic studies which characterized the biological mechanisms of PLCS and the pharmacology of milrinone. Dr Edward Bell (MPI) has an extensive record in leading multicenter clinical trials and the Data Coordinating Center (DCC) PI Dr. Abhik Das has led several NHLBI funded trials. Innovation: In most centers PLCS is recognized late, when hypotension is severe, and prompts use of vasopressor drugs which impair heart function. There are no prior randomized clinical trials of milrinone after PDA closure; therefore, neither treatment efficacy nor long-term safety is known. We propose a randomized controlled trial (RCT) to evaluate the immediate benefits of milrinone in decreasing the rate of PLCS and 7-day mortality. The need to assess long-term outcomes of RCTs is compelling to ensure treatment safety. Approach: We will perform a RCT in preterm infants born less than 28 weeks’ gestation asking: “Does routine use of intravenous milrinone lower the risk of PLCS or mortality within 7 days of intervention and is treatment safe?” The question is relevant to the mission of NHLBI and aligns with parental values to minimize postprocedural risk. In addition, it represents a paradigm shift in Neonatology to conduct clinical trials of treatments that offer biologic plausibility in illnesses that have been mechanistically characterized. Environment: We have partnered with the NICHD Neonatal Research Network (NRN), which includes 15 clinical centers, and have added 4 additional sites to maximize enrollment capabilities. We believe this trial is both feasible and achievable based on the prior track record of NRN in completing meaningful clinical trials.

NIH Research Projects · FY 2026 · 2024-06

Malaria, caused by Plasmodium species, is an unresolved global health burden. Although insecticide treated bed nets and antimalarial drugs have reduced the incidence and severity of malaria in some regions, infections are on the rise with 247,000,000 cases and >600,000 fatalities in 2021. Of additional concern, front line artesminin drug therapies are threatened by emerging drug resistant parasites. Thus, effective vaccines remain a critical goal to combat the global threat of malaria. Due to logistics and the development of Controlled Human Malaria Infection (CHMI) challenge in humans, most initial clinical trials of candidate vaccines are carried out in malaria naïve individuals rather than in malaria endemic regions. Unquestionably, the most successful of these candidates are Radiation Attenuated Sporozoites (RAS). RAS vaccination, originally described in mice, elicits pre-erythrocytic (liver-stage) immunity that can completely prevent development of symptomatic blood-stage infection after exposure to virulent sporozoites in humans3. RAS vaccination (by the i.v. route with cryopreserved RAS) in malaria naïve individuals can be up to 100% effective and immunity can last for at least a year. However, a major hurdle for progress in malaria vaccines is the finding of substantially reduced efficacy of RAS vaccination in malaria endemic regions To address this knowledge gap, we generated a mouse model where prior exposure to non-lethal P. yoelii 17XNL (Py) blood-stage infection compromises P. berghei ANKA (Pb) RAS-induced protective immunity against virulent Pb sporozoite challenge (Please see Fig. 1 for experimental design schematic). We further show that prior malaria exposure results in a prolonged (>12 month) reduction in the capacity to make malaria-specific CD8 T cell responses against RAS immunization. In considering how such durable immune dysfunction could occur, we noted that one long-term signature of malaria exposure in humans and mice is the essentially lifelong persistence of hemozoin (Hz) in specific tissues (liver, spleen, bone marrow). Hz is a non-degradable biocrystal formed during blood-stage infection as Plasmodium metabolizes hemoglobin in infected RBC. Importantly, we determined that injection of synthetic Hz and equilibration in tissues also compromised CD8 T cell responses to RAS immunization. The goal of this RO1 is to gain mechanistic insight into Hz-mediated T cell dysfunction in an effort to improve the efficacy of malaria vaccines in endemic areas. Aim 1. Determine how Hz disrupts antigen-presenting functions required for CD8 T cell priming after RAS immunization. Aim 2: Define the extent to which Hz compromises RAS- induced liver T resident memory (Trm) and circulating T cell memory (Tcircm) protective functions. Aim 3. Identify translatable immunization regimens to overcome Hz-mediated disruption of CD8 T cell priming and liver stage immunity after RAS vaccination.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Host transfer RNAs are cleaved into fragments during infection by diverse bacteria and viruses, yet what triggers this molecular event and how tRNA fragments (tRFs) impact infection remain poorly understood. This proposal leverages powerful molecular, genetic, and biochemical approaches during gammaherpesvirus infection to profile differential tRNA cleavage and to assess how tRNA cleavage and/or the resulting tRFs regulate the antiviral response. The overall objective in this proposal is to profile tRFs in infected primary cells and define whether tRNA cleavage or tRFs modulate gammaherpesvirus infection. This work explores the central hypothesis that tRNAs are cleaved in response to viral sensing and that gene regulatory functions of tRFs further establish an antiviral state. To test this hypothesis, Aim 1 employs a highly innovative sequencing strategy to accurately sequence tRNAs and their derivatives induced by gammaherpesvirus infection in primary, immune-competent cells. This aim will identify abundant, and likely functionally relevant, infection- induced tRFs, as well as introduce a sequencing tool with broad applicability to the tRF field. Aim 2 tests the hypothesis that tRF biogenesis is part of the host antiviral response by assessing gammaherpesvirus replication in response to decreased or increased expression of tRFs or tRNA endonucleases. These experiments will result in fundamental knowledge explaining why tRFs are generated in response to diverse viruses and reveal broad potential for tRNA-based antiviral therapeutic strategies. The work proposed here is significant, as it will pioneer the concept of antiviral tRFs, introduce a widely applicable sequencing strategy, and will ultimately reveal novel tRNA-centric nodes of gene expression control that can be manipulated to prevent and treat infectious disease.

NSF Awards · FY 2024 · 2024-06

This project addresses a question of profound consequence: How does the brain integrate information about the present with the past to predict the future? Human and nonhuman animals rely on memories of the past to anticipate the future, weighted by the reality of the present in our ever-changing sensory world. As universal as it is for neural systems to integrate information from the past and present to forecast the future – and the striking impact on quality of life when these functions fail – how the brain achieves this is unknown. To better understand memory and prediction, this project takes a cross-species approach and examines brain activity in the human and non-human primate. In addition, the collaborative research teams have planned outreach activities to rural and urban communities that promote neuroscience. This binational, collaborative project combines expertise from researchers in the United States and United Kingdom and takes a novel approach to study a brain system implicated in memory and future prediction. The goal is to study this system in nonhuman primates in ways that cannot typically be studied directly in humans, and to directly compare the results to humans through the study of neurosurgery patients. The aim is to directly compare cross-species data using complementary analyses so that the required animal research is directly and immediately relevant for understanding the human brain. The research may eventually also lead to societal benefits by advancing approaches to compensate for impairments in hearing, memory or prediction. Furthermore, these unique cross-species data will be openly shared and may contribute towards developing better machine learning approaches, as well as further discovery and innovation by the global community. This project is awarded under the SBE-UKRI Lead Agency Opportunity. 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 · 2024-06

PROJECT SUMMARY Molds cause devastating infections in diverse patient populations worldwide. The most life-threatening of these diseases are invasive mold infections (IMIs) which primarily affect immune compromised individuals including those undergoing chemotherapy, long term steroid treatment, and hemopoietic or solid organ transplant patients. IMIs can be caused by a handful of environmental molds but the most common species is Aspergillus fumigatus. Currently, there are three classes of antifungals used to treat IMIs; however, despite available treatments, mortality rates remain unacceptably high, typically ~50% but reaching 80-100% for some mold species and patient cohorts. One contributing factor to the high mortality rates is intrinsic resistance of some mold species to some or all clinical antifungals. In addition, acquired antifungal resistance, particularly among A. fumigatus isolates, is becoming a clinical problem worldwide. In the drug development space, antifungal drug screens often focus on yeast species. This is due in part to the technical ease of handling these organisms in high-throughput settings. Yeast growth is tightly correlated to optical density, facilitating large-format growth-based screens. In contrast, molds grow as filaments which create a heterogenous culture of tangled cells whose optical density is not well correlated to biomass. Additionally, the inability to handle these cultures with automated liquid handling devices creates additional challenges in high throughput settings. However, the high mortality rates and limited activity of clinical antifungal against molds warrants more focus on these organisms in antifungal drug screening. To address the need for mold-active antifungals, we developed and validated a high-throughput compatible screening assay to screen directly with A. fumigatus. This luciferase-based assay measures the release of the cytosolic enzyme, adenylate kinase (AK), as a readout for fungal cell lysis. Uniquely, when used with A. fumigatus this assay can also detect compounds that inhibit germination through the suppression of background AK release that occurs during normal germination and vegetative growth. Here, we propose a high- throughput screen of a large library of synthetic, drug-like molecules for novel scaffolds with anti-mold activity using our AK screening platform. Pilot large-format screens have already identified candidate molecules for further development; thus, based on the scale and diversity of our proposed screen, we expect to identify additional mold-active antifungals with novel mechanisms of action for preclinical development.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Perinatal mental health conditions are the most common complication of pregnancy and childbirth (1 in 8 women). When left untreated, perinatal depression and anxiety adversely affects the entire family with pregnancy complications and negative outcomes including preterm birth, impaired mother-infant bonding, impaired lactation, substance abuse, divorce, suicide, and infanticide. Our previous and extensive work with multilevel stakeholders including well-established community advisory boards, underrepresented and minority women in rural geographies, and state departments of public health demonstrates the importance of social support as a mechanism for improving outcomes in perinatal depression, particularly in rural geographies. Home visiting programs (HVPs) can provide the social support needed to improve mental health outcomes in pregnant and postpartum women. Despite the known benefits of HVPs and the high rates of moderate to severe depressive symptoms among HVP recipients, home visitors report that clients with depression are more difficult to engage; a specific need exists to address perinatal mental health in HVPs. Mothers and Babies, trialed in HVPs by our co-investigator, is an evidence-based cognitive behavioral intervention that has been shown to be effective in reducing depressive symptoms, but barriers remain for maximizing adoption and fidelity within HVPs. Using an evidence-based implementation strategy that tailors implementation delivery to the needs of the specific populations and context may improve fidelity and adoption, particularly in rural states where residents have limited access to care. Our long-term goal is to improve uptake of an evidence-based maternal mental health intervention to reduce adverse maternal outcomes and improve community health. The objectives of our study are: Aim 1: Adapt implementation facilitation to support uptake of Mothers and Babies using stakeholder input; Aim 2: Analyze the effects of the adapted facilitation on implementation outcomes (i.e., adoption and fidelity) using mixed rapid ethnographic methods; and Aim 3: Determine the effect of adapted facilitation on the clinical outcomes of severity of depressive symptoms and perceived stress. We will conduct a hybrid implementation-effectiveness-context cluster randomized control trial to test the adapted facilitation strategy compared with implementation as usual (i.e., standard education). The immediate impact of this research will be to show whether adapted facilitation can improve the uptake and fidelity of a maternal mental health intervention like Mothers and Babies across multiple HVP models and thus positively affect depressive symptoms and perceived stress of recipients. Further, our implementation protocol can be used by other states to better integrate other maternal mental health interventions into HVPs, leading to further improvements in maternal mental health and further reductions in adverse outcomes for mothers, children, and families.

NIH Research Projects · FY 2025 · 2024-06

T cells in the brain have long been associated with pathogenic outcomes, with the healthy brain considered an immune privileged organ. This concept has recently been overturned with the description of meningeal lymphatics, roles for immune cells in normal brain homeostasis, and detection of T cells in the brains of healthy subjects and in aging subjects with neurological disease. Why these T cells are in the healthy brain and what role they play in this critical tissue remain major knowledge gaps. Due to their abnormally hygenic housing conditions, young adult SPF mice display peripheral immune systems that resemble infant cord blood. In contrast, signatures of repeated microbial exposure are already evident in children and young adult humans and these signatures intensify with age. Specific to this proposal, young adult SPF mice, which are the subjects in many if not most animal models of neuroscience research, have low numbers of T cells in their brains at homeostasis. Several models have been implemented to “normalize” the peripheral immune system of inbred SPF mice to better mimic humans. One informative approach, to generate such “dirty mice” leverages the co-housing (CoH) of SPF mice with pathogen-infested “pet store” mice to permit natural transfer of mouse pathogens. Alternatively, repeated exposure of SPF mice to known laboratory pathogens (Specific Pathogen Exposed, SPExp mice) has emerged as a tractable approach that can be used at lower biocontainment than the CoH approach. Studies with these models have largely focused on understanding how “normalization” of the immune system influences peripheral immune responses to infection or tumors within lymphoid organs and barrier tissues. Thus, the impact of repeated microbial exposure on the generation of brain-surveilling T cells is currently unknown. Our preliminary studies reveal that not only does repeated microbial exposure normalize the peripheral immune system, it also results in substantial and specific increases in memory CD4 and CD8 T cell numbers in the brain. In parallel, our preliminary data show here that brain-residing T cells interact with other immune cells in the CNS, including CD11c+ dendritic cells (DCs), that perform essential functions during brain homeostasis and in response to brain trauma, infections, tumors, and neurodegeneration. Due to the heavy reliance on SPF mice for studies of brain function, the consequences having “normalized” populations of brain-residing memory T cells during homeostasis or neurological disease remain unknown. Our long-term goal is to exploit models of repeated microbial exposure to “normalize” the immune system and understand the roles of brain-residing memory T cells in shaping brain function and neuroimmune responses. Specific Aim 1. Determine how “normalized” numbers of brain-residing CD8 and CD4 T cells impact the functional status and cellular interactions of brain microglia and CD11c+ DCs at homeostasis. 1.1. Determine the epigenetic and transcriptomic landscape of myeloid cells in SPF and SPExp mice. 1.2. Visualize the spatiotemporal dynamics of direct T cell-myeloid interactions in vivo in SPF and SPExp mice.

NIH Research Projects · FY 2024 · 2024-06

Despite advances in diagnostic and therapeutic modalities, the 5-year survival of patients with pancreatic adenocarcinoma (PDAC) remains woefully low. Unfortunately, African Americans (AA) bear a significant brunt of this disease and both the incidence and mortality of PDAC are higher amongst them. Understanding the biological factors contributing to this pattern will help develop novel strategies to improve outcomes. Pancreatic cancer is a mutation-driven cancer. Alterations in tumor driver genes like KRAS, TP53, SMAD4 and CDKN2A alter multiple transcriptional pathways in the native pancreatic cells and their microenvironment, resulting in tumor growth, progression and metastases. Presence or absence of many of these mutations can modulate the aggressiveness of cancer and the clinical course of patients with PDAC. Studies in other cancers including colon, breast and prostate cancer, have demonstrated that genomic and transcriptional landscape can shape the incidence and the outcomes of these cancers. However, such data in the context of PDAC is lacking. Thus, we have put forth the following hypothesis to explain the observed clinical patterns in the context of PDAC: Hypothesis: Differences in the genomic and transcriptomic signatures contribute to the observed patterns of increased pancreatic cancer incidence and worse outcomes in AA patients. Our hypothesis will be tested through the two specific aims: Aim 1 will be focused on interrogating the mutational landscape of PDAC using deep whole exome sequencing (WES) on resected tumor specimens of histologically proven PDAC cases from AA patients. In addition to testing specific hypotheses about KRAS, we will screen potential pathogenic variants (PPVs) which could be contributing significantly clinical outcomes among PDAC patients. In Aim 2 Bulk RNA sequencing (RNA-seq) will be performed on the cohort of 100 PDAC specimens from AA patients (from aim 1) to identify clinically relevant transcriptional pathways in PDAC tumors in two ways. First, the PDAC cases will be compared according to our published PurIST algorithm to understand the incidence of classical/basal tumor subtypes, which predict response to frontline therapy. Additionally, we will perform denovo transcriptomic subtyping and pathway analysis to understand whether PDAC tumors harbor distinct transcriptional signatures compared to those previously identified. Successful execution of the current studies will provide, for the first time, detailed integrative analysis of genetic and transcriptional landscape of PDAC. These data will help improve our understanding of the biological factors contributing to observed clinical patterns and support the development of novel strategies to improve outcomes.

NIH Research Projects · FY 2025 · 2024-06

ABSTRACT While anti-VEGF (vascular endothelial growth factor) therapy has been a watershed for the treatment of wet AMD (age-related macular degeneration), approximately 50% of patients receiving anti-VEGF therapy exhibit persistent disease activity, which can include persistent fluid exudation (edema), fibrosis, hemorrhage, and limited vision recovery. Blocking VEGF only addresses the formation of leaky and new vessels, but not fibrosis. Reducing fibrosis in concert with blocking leakiness and vessels may preserve vision and stop progression of neovascular AMD. Our long-term objective is to develop a translatable delivery system for AMD that can address the multifactorial nature of the disease and can be adjusted remotely via ultrasound for on-demand treatment as needed. Our objective in this project is to focus on the sustained delivery of two drugs that have been shown to address two of the critical components of wet AMD: neovascularization and fibrosis. We propose to deliver acriflavine, a HIF-1alpha inhibitor that prevents neovascularization in the eye, with pirfenidone, an antifibrotic drug, via a long-term delivery system based on polyurethane nanocapsules that deliver each drug over a prolonged period of time and can be triggered for on-demand release using ultrasound. We hypothesize that the controlled, long-term delivery of these two molecules in concert will lead to better, long-term outcomes including preservation of retinal tissue and visual acuity.

NIH Research Projects · FY 2025 · 2024-06

Whether accidental or intentional, ionizing radiation (IR) exposure poses significant risks to thoracic organs, particularly the heart and lungs. It can lead to inflammation, fibrosis, and cellular senescence, resulting in a range of clinical complications. These include pericarditis, coronary artery disease, valvular issues, heart failure, arrhythmias, radiation pneumonitis, pulmonary fibrosis, and even mortality. Notably, there are sex- based differences in how individuals respond to IR, with women often displaying greater susceptibility to long- term IR toxicities. The exact mechanisms behind these sex-based disparities are still unclear, but they may involve factors such as hormones, genetics, and metabolism. Nitric oxide synthase 1 plays a crucial role in catalyzing nitric oxide biosynthesis. Preliminary research in mice exposed to 20 Gy cardiac-targeted IR showed that they developed heart and lung abnormalities, including diastolic dysfunction, conduction issues, cardiac fibrosis, and pulmonary congestion. However, male mice exhibited additional problems including left ventricular dilation, systolic dysfunction, and alterations in mitochondrial electron transport chain complex II activity. Interestingly, both male and female mice with decreased nitric oxide synthase 1 expression exposed to 20 Gy experienced reduced left ventricular size and function, faster atrioventricular conduction, and no evidence of diastolic dysfunction. Treatment with a superoxide dismutase mimetic, Rucosopasem, mitigated some of the IR-induced cardiac changes in female mice. This data implies that sex-related differences in nitro-oxidative pathways and disruptions in the mitochondrial electron transport chain metabolism could influence sensitivity to cardio-thoracic IR. We hypothesize that IR-induced, sex-dependent alterations in redox signaling pathways stemming from differences in mitochondrial electron transport chain activities between males and females lead to changes in reactive oxygen species and reactive nitrogen species, which in turn mediate IR-induced cardiac and pulmonary dysfunction. Aim 1 will use an upper body model of IR exposure to investigate the sex-based effects of IR on mitochondrial oxidative metabolism in wildtype and heterozygous nitric oxide synthase 1 disrupted mice, its role in generating reactive oxygen and reactive nitrogen species, and its impact on cardio- pulmonary function. Aim 2 will assess the effectiveness of Rucosopasem, a superoxide dismutase mimetic, in mitigating IR-induced effects on the cardio-thoracic system in both male and female wildtype mice exposed to upper body IR. Completing these studies could unveil sex-based disparities in redox metabolism and mitochondrial dysfunction, potentially offering targets for preventing or reducing IR-induced cardio-pulmonary toxicities. Rucosopasem might also emerge as a novel therapeutic approach for radiation mitigation.

NIH Research Projects · FY 2025 · 2024-05

Long-COVID has emerged as a serious long-term complication of COVID-19 affecting ~10% of adults in United States. Recent estimates suggest that approximately 7–8% of U.S adults have experienced long COVID at some point, with about 3–4% currently affected. While these percentages may seem modest, they translate to millions of individuals experiencing persistent symptoms such as fatigue, pain, and cognitive difficulties, often leading to substantial impairment in daily functioning and quality of life. The burden is even greater in a subsets of population individuals with preexisting health conditions such as sickle cell disease (SCD). Sickle cell disease is a life-threatening disease affecting 1 in 365 African Americans (AA). It is characterized by chronic hemolytic anemia, vaso-occlusive crisis, acute chest syndrome and multiorgan damage. Evaluating long COVID in patients with SCD is particularly challenging as many symptoms of long-COVID including fatigue, pain, and organ dysfunction overlap with chronic complications of SCD, making it difficult to distinguish between the two conditions. There is limited research, and a lack of validated tools specifically designed to assess long-term COVID-19 effects in the SCD population, leading to gaps in understanding and under-recognition of long-COVID in these patients. These knowledge gaps hinder our ability to implement targeted early interventions (e.g., surveillance, vaccine, antivirals) to mitigate the long-term impacts of COVID-19 in high-risk SCD patients. Consequently, the prevalence and morbidity caused by the long-COVID, the post-acute sequalae of SARS-CoV-2 (PASC), is unknown in SCD population. Proposed study will address these knowledge gaps using a data-driven strategy. Our main objective is to characterize the long-term outcomes of COVID in SCD patients with specific focus on long COVID. Our Aim 2 is to characterize the subphenotypes of long COVID in the AA with SCD and determine if differences exist compared to the general population. We leverage upon NIH initiated National COVID Cohort Collaborative (N3C), a harmonized EHR repository. This registry is representative of US population with ~40 million patients [SCD patients, 15,169; COVID positive SCD patients, 4,143]. For diagnosis and phenotyping of long COVID, we will conduct cluster analysis of the individuals in the SCD with COVID-19 cohort with a potential diagnosis of long COVID [ICD-10 U0.09] using unsupervised machine learning methods and the Human Phenotype Ontology-encoded EHR data. We will evaluate the association of cluster membership with a range of pre-existing comorbidities and with measures of acute COVID-19 severity. These analyses will identify clinical characteristics of the sub-phenotype clusters or groups of long-COVID in AA with SCD and compare it with general population. Knowledge gained from this analyses will advance precision diagnostics by applying ML, a subtype of artificial intelligence, to characterize subphenotypes of PASC in SCD population. Upon completion, our study will provide real-world data to guide both clinical practice and public policymaking for preventing and managing long COVID in SCD people. Future studies will focus on identifying the predictors of long COVID and understand how it affects SCD comorbidity. Collectively, these discoveries will improve management of long COVID in SCD population.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Almost half of Americans over 30 years old have periodontitis, and 9% have severe periodontitis, which can lead to bone loss, loss of teeth and osseointegration failure of dental implants. Current treatments for periodontitis, including the standard scaling and root planing combined with systemic or local administration of antibiotics, do not effectively address safety concerns, adequately prevent periodontal bone loss, or repair damaged bone structures. Tissue engineering using stem cells/genes/proteins, combined with biomaterials, is a promising strategy to address the challenges in periodontal bone regeneration despite the numerous hurdles that still remain. Our primary goal, in collaboration with Dr. Shaoping. Zhang—a periodontist at University of Iowa with extensive expertise in both basic and clinical research in periodontitis—is to develop an innovative and translational biomaterials-based strategy to prevent and treat periodontitis-induced bone loss. PI Sun’s pilot study indicates that the cell-permeable metabolite AKG (DMAKG) significantly inhibits osteoclastogeneis and inflammation and promotes osteogenic differentiation in vitro. A hydrogel-delivered local DMAKG promotes bone regeneration in aged mice, which is challenged by chronic inflammation. Moreover, we developed a new vanillin/bioglass-based technique to fabricate an injectable chitosan hydrogel (CVB) with powerful antimicrobial and osteogenic abilities. Thus, our central hypothesis is that an innovative, injectable, and biodegradable chitosan hydrogel that locally releases the metabolite AKG can effectively prevent and treat periodontitis- induced bone loss in a clinically relevant mouse model by simultaneously reducing bacterial infection, inflammation, and osteoclastogenesis while promoting osteogenesis. In Aim 1, we will develop a novel injectable DMAKG-releasing chitosan hydrogel that can reduce harmful microbial counts, inflammation, and osteoclastogenesis while improving osteogenic capabilities in vitro. In Aim 2, we will establish the effectiveness of a treatment for periodontitis-induced bone loss using a novel chitosan hydrogel-mediated DMAKG release in a mouse model. At the completion of this exploratory/developmental R21 project, we will have developed a novel periodontitis treatment using an injectable chitosan hydrogel that locally releases the metabolite AKG. Our novel strategy will simultaneously reduce 1) bacteria growth, 2) chronic inflammation, 3) osteoclastogenesis, and 4) promote osteogenesis, which are all important for effective treatment of periodontitis, but current treatments have difficulty targeting them all. Our acellular biomaterials and metabolite- based strategy for periodontitis treatment has greater translational potential than using biological mediators.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Schoolteachers' voice problems are significant, not only because these problems occur so frequently but also because they undermine education in the classroom. Research has suggested a number of associated physiological, environmental and behavioral risk factors. However, there remains a fundamental gap in understanding how these factors affect a teacher's vocal health over an academic year, how teachers accommodate to the vocal demands they face, and how current occupational policies (including the financial and attitudinal constraints of educational policy makers) impact teachers' vocal health for better or worse. The continued presence of this gap represents a barrier to the long-term objective of proactive vocal health education and treatment programs. The current proposal will move this effort forward by exploring how teachers' voices are impacted by vocal risks, vocal demands, vocal accommodations, and vocal health policies. Grounded on strong foundational work and a track record of productivity, this experienced research team proposes 3 specific aims: [1] determine the interactions between risk factors related to the occurrence of teacher voice problems by collating cross-sectional and longitudinal (year-long) survey data with standard voice assessments; [2] quantify teachers' perceptual acuity of and accommodations to classroom vocal demands that increase the risk of vocal health issues by conducting analyses in classrooms and simulated classroom environments; and [3] investigate current and potential school-based policies to improve vocal health by reviewing administrative responses to teachers' voice issues and quantifying the costs of both solutions and non-interventions. The proposal is innovative in part because it [1] merges virtual reality technologies with previously tested acoustic simulations and real-time auralization systems to replicate classroom risk factors and interventions, eliciting “teacher voice” in controlled settings; [2] uses tools from a unique interdisciplinary research team (i.e. Voice Science, Acoustical Engineering, Communication, Economics, and Education) to approach a significant public health concern in an effectively innovative way; and [3] combines reliable survey instruments (developed using focus groups) with standard clinical assessments to accurately track how a teacher's voice changes over the course of a full academic year. While not a clinical trial, these data are clinically significant because patterns may emerge, including when voice problems occur, how they progress over an academic year, and why they improve or worsen. Thus, this ambitious approach will help preserve teachers' vocal health, improve the response when problems present, and indirectly improve the classroom learning environment. The results of this study will also provide school administrators and other policy makers with practical and economically feasible information that can be used to support teachers' vocal health in their districts.

NIH Research Projects · FY 2026 · 2024-05

Although best known for its role in Alzheimer disease, the tau protein is a significant driver of neuronal network dysfunction in neurodevelopmental disorders, including epilepsy and autism, which have a devastating lifelong impact on function and quality of life. Tau phosphorylation, detachment from microtubules, and toxic gain of function are significant drivers of pathology in hypoxic-ischemic injury and two of its major developmental sequelae: epilepsy and autism. Despite these toxic effects, tau is strongly evolutionarily conserved through the entire mammalian lineage, suggesting that it has a physiologic function. Although tau knockout has been studied extensively in mice, these studies are difficult to translate to humans because human tau has a unique N-terminus insert in a region critical to tau localization and interaction with NMDA receptors (NMDAR). Tau is a promising therapeutic target for multiple neurodevelopmental diseases, including autism, epilepsy, and early- life hypoxic-ischemic injury. While the efficacy of tau-reducing agents in AD is controversial, they are safe in adults and highly effective at reducing tau levels. This represents an unprecedented opportunity to adapt drugs developed for Alzheimer disease for use in neurodevelopmental disorders. To ensure the safety of this strategy in the developing brain, however, there is a critical need to understand the neurodevelopmental function of the tau protein in an entirely human model system. Without this knowledge, developing safe and effective tau- targeted therapies for these diseases is unlikely. Our long-term goal is to develop safe and effective tau- targeted therapies for neurodevelopmental disorders. Our overall objective for this proposal, as a first step to achieving this goal, is to determine the physiologic role of tau during neurodevelopment. We hypothesize that tau is necessary for dendritogenesis in the developing human brain due to a human-specific N- terminus insert that upregulates tau-NMDAR signaling. This hypothesis is based on our preliminary data demonstrating impaired dendritogenesis in human tau knockout neurons and a vital role for the human-specific tau N-terminus insert in interaction with fyn kinase. It is supported by published literature showing that tau-fyn interaction upregulates NMDAR signaling. This process leads to neurotoxicity in the postnatal brain, but NMDAR signaling is necessary for dendritogenesis and dendritic arborization in the developing brain. We will test our hypothesis by pursuing the following specific aims: (1) Determine the role of tau-NMDAR interaction in human neuronal maturation and (2) Determine the role of the human-specific N-terminus insert in human neurodevelopment. At the completion of the study, our expected outcomes are that we will have identified a critical developmental function of the human tau protein and determined the role of the human-specific n- terminus tau insert. These results will have a significant positive impact because they are a necessary first step to determining the safe window for therapeutic tau reduction in neurodevelopmental disorders and because they would identify a previously unknown human-specific physiologic function of the tau protein.

NIH Research Projects · FY 2025 · 2024-05

ABSTRACT Inherited retinal degeneration is a class of disease characterized by progressive photoreceptor cell death and irreversible vision loss. While multiple treatment options are being explored, the preferred approach will depend on how far a patient's disease has progressed at the time of diagnosis. For patients who have lost most of their photoreceptor cells and no longer have useful vision, photoreceptor cell replacement therapy will be required. Use of pluripotent patient-derived stem cells to generate transplantable photoreceptor precursor cells is a promising approach that is being aggressively developed. Robust retinal differentiation protocols that enable production of 3D retinal organoids have been reported and adapted to current good manufacturing practices. While retinal organoids contain therapeutically relevant photoreceptor precursor cells, they also contain all the other cell types present in the neural retina. As such, photoreceptor cell enrichment is required in order to achieve optimal treatment outcomes. Photoreceptor cell enrichment has been achieved via the use of fluorescence activated cell sorting and magnetic bead-based pull down, both of which typically rely on the use of cell type specific antibodies that target cell surface antigens. While highly effective, these approaches are challenging to adopt to clinical manufacturing of autologous products. Given that photoreceptor cells naturally segregate to the outermost layer of retinal organoids, we have found that partial organoid dissociation can be used to isolate a relatively pure photoreceptor cell population. While encouraging, we believe that the rate at which retinal organoids dissociate will vary between patients and be highly dependent on organoid shape and size as well as the lot of enzyme being used. For clinical use, the manufacturing process should result in a final product that consistently meets a predetermined set of clinical release criteria with little variability across production runs. As such, standardization of our partial dissociation protocol and validation of the final cell product is essential. To address these needs, in this application we propose two specific aims. In Aim 1, we propose to refine our partial retinal organoid dissociation protocol and identify the optimum tradeoff between photoreceptor cell purity and recovery that is achievable without antibody-based sorting. In doing so, we will fully characterize the identity of all cell types within the final preparation and determine the size and mechanical properties of therapeutic photoreceptor precursor cells. In Aim 2, we propose to fabricate a retinal organoid dissociation and label-free microfluidic photoreceptor cell enrichment platform designed to reduce the amount of time that individual photoreceptor cells spend in dissociation enzyme, enable further photoreceptor cell enrichment, and to permit empirical determination of organoid dissociation state. Specifically, by incorporating electrodes into a microfluidic channel, we believe we will be able to monitor organoid dissociation rate in real time via the Coulter principle. Despite differences that may exist between patients, rounds of differentiation, or reagents used, we hypothesize that real-time monitoring of dissociation will allow us to identify when the process should be halted in order to achieve a consistent, high purity product without the need for further label-based sorting.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT My long-term goal is to improve the toxicity profiles for cancer therapeutics. One-third of cancer patients treated with the commonly prescribed chemotherapeutic 5-fluorouracil (5-FU) experience severe and life- threatening toxicity to standard doses of the drug. An appreciable fraction of those patients die—not due to cancer, but because of side-effects related to treatment. Clinical studies indicate that the majority of patients who experience severe toxicity to 5-FU are deficient for an enzyme called dihydropyrimidine dehydrogenase (DPD, DPYD gene); however, only four genetic variants in DPYD have been adequately characterized to be considered predictive of 5-FU toxicity in clinical studies. My preliminary studies demonstrate that these four variants explain only a small fraction of severe 5-FU toxicities and have exceedingly limited clinical value outside of individuals with European ancestry. The primary objective of the studies proposed in this grant application is to identify additional biomarkers of 5-FU toxicity risk that can be used to individualize 5-FU dosing with the goal of improving the safety profile for the drug. My overall hypothesis is that expanded biomarker-based pre-treatment tests will more accurately identify patients with DPD deficiency, as well as the relative degree to which the DPD function is impaired, enabling more accurate dose optimization. My rationale is that improved biomarker-based approaches to dose individualization have strong potential to improve the safety profile for this commonly used therapeutic. Aim #1 will identify risk alleles for severe 5-FU–related toxicity in understudied populations. Aim #2 will characterize multi-marker haplotype contributions to 5-FU toxicity. In Aim #3, I will develop an integrated predictive model of 5-FU toxicity using deep machine learning. It is my expectation that the proposed studies, which will leverage multiple large patient and volunteer data and specimen collections to address various aspects of my primary hypothesis, will answer key questions that have vexed pharmacogenetics researchers for decades. In doing so, the proposed studies are expected to identify clinically relevant biomarkers that can be used to improve the safety profile of 5-FU through dose optimization.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Diabetic nephropathy (DN) is the most prevalent acquired glomerular disease, affecting ~1 in 3 people with diabetes. DN is characterized by a progressive proteinuric podocytopathy leading to 30-50% of the cases of end stage kidney disease in the United States. Limited understanding of the pathogenic mechanism constrains therapy to slowing the progression instead of preventing the pathogenesis of DN. Podocytes maintain the glomerular filtration barrier by forming a molecular sieve called the slit diaphragm (SD). Mistrafficking of SD proteins, which causes their dyshomeostasis is an early event in diabetic podocyte injury. There is a critical need to define the early trafficking mechanisms underlying the diabetes-disturbed proteostasis in podocyte, to identify targets that inform therapies to prevent rather than postpone the progression of DN. Our recent work implicates a unique role of dynein as an energy-responsive motor protein complex that transduces diabetic signals into disturbed trafficking and proteostasis in podocytes. Hyperglycemia can trigger the expression of dynein subunits, apparently via a shared regulation by energy-responsive kinases and transcription factors (TFs). Forceful transient overexpression of these hyperglycemia-responsive dynein subunits recapitulates the features of diabetic podocytopathy. Our goal of this proposal is to dissect the targetable mechanisms of dynein-mediated trafficking disturbance that compromise the function and viability of podocytes, to guide development of therapies to prevent DN. Our central hypothesis is that dynein mediates an energy-responsive trafficking that causes diabetic podocytopathy with dyshomeostasis of proteins important for podocyte function. Furthermore, we posit that this pathology can be attenuated by targeting the metabolism-responsive regulators of dynein expression or activation. The specific aims include: (1) Determine how diabetes enhances dynein expression and activity underlying podocytopathy. By analyzing the posttranslational modifications of the TFs and epigenetic modifications of dynein gene promoters in conjunction with ChIP and reporter gene assays, we will test whether diabetes activates dynein expression via SP/KLF family TFs modified by energy responsive kinases and whether dynein-mediated trafficking can be reversed by targeting the TFs and kinases. (2) Elucidate how dynein-mediated trafficking disturbs podocyte proteostasis in diabetes. Using live cell and pulse chase-based trafficking and degradation assays, we will test whether dynein has a key role in mediating the energy-responsive changes in protein trafficking that disturb proteostasis. (3) Remodel dynein activity to see if it mitigates podocytopathy in diabetic mouse models. Using a mouse model with podocyte-specific overexpression of Dctn1 (a subunit required for dynein activation), we will test whether activating dynein directly causes podocytopathy. Using a transgenic mouse model with a podocyte-specific knockout of Dctn1, we will test whether targeting dynein-driven pathogenesis can attenuate diabetic podocytopathy. A detailed understanding of dynein’s pathogenic role in DN will facilitate the development of new therapies to prevent DN.

NIH Research Projects · FY 2026 · 2024-05

The goal of this proposal is to develop and integrate a high spatial/spectral resolution reproducible whole-brain magnetic resonance spectroscopic imaging (MRSI) framework on 3T scanners to improve our understanding of metabolic changes that occur in Alzheimer’s disease and related dementias. While MRSI has been shown to provide great utility to study metabolic changes associated with neurodegenerative disorders, its widespread adaption as a clinical tool has not been realized due to several technical challenges, such as low sensitivity, low spatial resolution (often just single voxel), B0 field inhomogeneity, and lack of complete integration with the scanner. The goal of this study is to develop novel methods of acquiring, processing, quantifying, and analyzing MR spectral data that overcome these technical challenges. This work will be undertaken by a collaborative team of investigators from the University of Iowa, University of California San Francisco, and GE Healthcare. To achieve our goals, we are proposing the following specific aims: 1) Develop and validate a high-resolution 5D MRSI framework on 3T scanners; 2) Develop tools for quantitative regional assessment of MRSI data; and 3) Evaluate the reliability and utility of the MRSI tools in a cohort of mild cognitive impairment (MCI), early Alzheimer’s disease, and a matched control sample without memory issues. Aims 1 and 2 will generate a normative metabolic atlas for ages 40-80 years old, which is composed of equal representation by sex. The resulting tools will also be applied to Aim 3 to evaluate brain metabolic profiles in MCI and early Alzheimer’s disease as compared to the matched control sample. The successful completion of this proposal will result in a whole brain MRSI protocol capable of collecting high quality data in less than 20 minutes, which can be used to study metabolic changes associated with Alzheimer’s disease and related dementias. The tools developed here will be distributed through the GE collaboration portal where they will be shared as a work in progress (WIP) package where feedback from the broader user community will be gathered to further refine the tools. In addition, the tools will also be distributed in an open format allowing them to be readily ported to MR scanners from other vendors. Ultimately, the tools will provide the ability to identify metabolic changes that occur in the brain associated with neurodegenerative disorders, which could be used to identify potential targets for new therapeutic agents as well as a marker for response to such therapies.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY While the amygdala is a key focus in psychiatric treatments and invasive modulation of amygdala activity has shown promise in treating certain refractory cases, its widespread use among millions of treatment-resistant patients is impractical and entails inherent neurosurgery-related risks. The development of transcranial magnetic stimulation (TMS) provides a potential noninvasive alternative. However, the effective modulation of the amygdala with TMS is hindered by the lack of knowledge in pinpointing a TMS-accessible cortical site that can reliably target and modulate the amygdala. The dorsolateral prefrontal cortex (DLPFC) emerges as a promising candidate for stimulation based on findings from extensive preliminary data, published work, and large human connectome datasets. The overall objective in this proposal to determine whether and how DLPFC repetitive stimulation modulates the amygdala activity with an unparalleled combination of invasive and noninvasive stimulation and recording methods in humans. The central hypothesis is that both invasive and noninvasive stimulation of DLPFC modulate the amygdala activity through their functional connectivity mechanism. This central hypothesis will be tested by pursuing three specific aims: determine invasive modulatory effects of intracranial stimulation of DLPFC on the amygdala recorded with intracranial EEG (iEEG) in epilepsy patients (Aim 1), translate stimulation with noninvasive TMS of DLPFC while tracking modulatory effects on the amygdala with iEEG in epilepsy patients (Aim 2a) and with functional MRI in healthy individuals (Aim 2b), and evaluate the role of DLPFC-amygdala functional connectivity in predicting modulatory effects of DLPFC stimulation on the amygdala (Aim 3). The proposed research is innovative, because it can determine a unique causal prefrontal pathway for noninvasive amygdala modulation in humans. It also represents the first attempt of any group worldwide to creatively combine multimodal cutting- edge brain stimulation and recordings to comprehensively evaluate modulatory effects of DLPFC stimulation on the human amygdala. The proposed research is significant because it is expected to provide compelling and conclusive causal evidence of amygdala modulation by DLPFC stimulation and inform a novel circuit- based strategy that can efficiently pinpoint a stimulation site within the DLPFC for noninvasive amygdala modulation. Ultimately, such knowledge will facilitate the rational design of personalized, circuit-guided noninvasive neuromodulatory therapies aimed at modulating the amygdala for psychiatric disorders.