Temple Univ Of The Commonwealth

NIH Research Projects · FY 2026 · 2026-06

Project Summary Cigarette smoking remains the leading cause of preventable disease and death in the United States. Emerging adulthood (ages 18–26) is a critical developmental period when lifelong patterns of tobacco use are often established. Despite population-level declines in smoking, these declines have not been equal, and significant differences persist in tobacco use across sociodemographic groups. This underscores the urgent need for innovative approaches to improve the reach and effectiveness of tobacco prevention and cessation efforts during this developmental period. We propose that to reduce tobacco use more effectively in this age group, it is necessary to understand and leverage the immediate social environment—specifically, the social relationships including peers, family, and close social ties that influence prevention and facilitate behavior change. However, the field lacks a clear understanding of how these micro-social dynamics interact with known psychosocial drivers of tobacco use. This project will use mixed methods to examine how psychosocial stress, social group identification, and the micro-social environment (i.e., network structure, social norms, and support) shape tobacco use trajectories and cessation outcomes in emerging adults. Our overarching goal is to identify modifiable drivers of persistent tobacco use that can serve as novel targets for future intervention development. In Aim 1, we use cross-sectional egocentric network interviews (N=600) to compare psychosocial stress and social network features across tobacco use statuses (never, current, former). In Aim 2, we follow a cohort of current smokers (N=350) over 12 months to evaluate how stress and network features predict cessation, including quit intention, attempts, and 7-day bioverified abstinence. For Aim 3, we will recruit a subset of this cohort for in-depth qualitative interviews with a purposive subsample of 12 ego networks from Aim 2 (N=36; 12 egos and up to 3 alters per ego) to examine how network structure and function influence quitting. The findings will be used to generate new insights for designing targeted, network-informed interventions to improve cessation outcomes across sociodemographic groups.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Although anal cancer is rare compared to other gastrointestinal cancers, its incidence and mortality have steadily increased over the past several decades. These trends disproportionately affect individuals with certain immunologic and behavioral risk factors, placing specific populations at markedly higher risk. Recent guidelines recommend targeted anal cancer screening based on individual risk, including annual digital anorectal exams (DARE), anal cytology with or without high-risk HPV testing, and follow-up with high- resolution anoscopy (HRA) for abnormal results. Despite effective prevention strategies, awareness remains low, stigma persists, and utilization of preventive services is uneven. This study will develop and evaluate a novel, peer-led social media intervention to promote anal cancer prevention in high-risk populations. Grounded in the Information-Motivation-Behavioral Skills (IMB) model, the Popular Opinion Leader (POL) model, and the SMILE Framework (“Social Media for Implementing Evidence”), the intervention will be co-designed with a community advisory board and delivered by trained influencers. The specific aims are: (1) Co-design and evaluate a peer-led social media influencer training program using adapted materials from a previously tested intervention and an evidence-based anal cancer prevention toolkit; and (2) Assess the feasibility and short- term impact of the resulting social media campaign. Using a mixed methods approach—including engagement metrics, social network analysis, qualitative interviews, and quasi-experimental methods—this study will generate essential data on the feasibility, acceptability, and potential impact of this scalable intervention. The long-term goal is to inform national communication strategies to reduce disparities in anal cancer.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT: Bipolar spectrum disorders (BSDs) are associated with major personal and public health burdens. Despite this heavy burden, the etiology of BSD is not fully understood. Further research on risk factors for BSD during adolescence, when likelihood of first onset of a BSD is highest, is needed to understand how BSD onset and symptoms can be better predicted and interventions delivered earlier. Determining the degree of risk for BSD conferred by various predictors is a vital step toward creating intervention and prevention programs that can identify individuals most at risk in order to reduce the likelihood of BSD onset, delay onset, or lessen course severity. Extant research has established several person-level factors that confer risk and influence dysregulation throughout the course of BSDs. The social and circadian rhythm model of BSDs posits that social and circadian rhythm dysregulation can result in mood symptoms and episodes. In another separate line of research, evidence suggests that hypersensitivity to rewards confers risk for BSDs. Researchers have suggested that the reward and circadian models of BSD risk and course can be combined into a joint, bidirectional model, such that disturbance in one of these systems, through a feedback loop, may promote dysregulation in both systems, contributing to mood symptoms and episodes. Additional theoretically and empirically supported predictors can be combined statistically with reward and circadian factors to better predict risk of bipolar symptoms. These factors include family history of BSDs, hypomanic personality, higher trait impulsivity, exposure to childhood adversity, affective lability, and substance use. However, the means by which predictive factors may be combined to better inform risk for bipolar symptoms is poorly understood. Although myriad risk factors for BSDs have been identified, little work has been done to statistically integrate information obtained through a multimodal approach to determine which individuals are most at risk. Thus, the proposed project seeks to evaluate empirically derived risk groups based on multimodal assessment of multiple risk factors for BSD during adolescence, a critical developmental period in which onset of BSDs is most likely. I will use participants from my sponsor's R01 study, which aims to examine the interplay of reward and circadian factors longitudinally to predict first onset of BSDs, add measures of additional risk factors, and statistically integrate these multimodal risk indicators with latent class analysis to evaluate the predictive utility of empirically-derived risk groups. My sponsors and I have designed a training plan involving coursework, workshops, experiential learning, and mentorship that will allow me to develop greater expertise in the development of mood pathology, learn advanced statistical methods required for this project, and gain the skills necessary for my future career as an independent clinical scientist. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Genital herpes simplex virus (HSV-1 and HSV-2) infections are painful and can result in transmission to sexual partners and newborns; the latter can be highly susceptible to severe disease with detrimental outcomes. While the host immune response mostly ensures that HSV remains in a latent state in dorsal root ganglions (DRG), fluctuations in immunity can allow the virus to escape effective immune surveillance. This can lead to infectious viral shedding from mucosal or skin sites where lesions may also develop. Strategies that fortify the natural immune response has the potential to limit frequency, degree and duration of HSV reactivation. This project will utilize CRISPR-Cas9 technology to attenuate HSV, while maintaining immune stimulation. The herpes protein pUL56 is encoded by late HSV-1/HSV-2 gene UL56. We and others have shown that pUL56 targets host cell protein degradation pathways, antagonizes innate immune sensing, and affects virulence in vivo. Recently, we demonstrated that a UL56 deletion HSV-1 mutant fails to cause secondary skin lesions and death in a mouse model. Interestingly, it still induces long-lasting protective immunity against infection with the wildtype virus. Importantly, as shown in new preliminary data, the deletion mutant is also attenuated in a vaginal infection mouse model. Thus, UL56 may represent a promising new therapeutic target. This MPI application leverages Dr. Jensen’s experience working with HSV infection models and the UL56 deletion HSV mutant virus and Dr. Kaminski's hands-on competence in developing and validating CRISPR-Cas9- based antiviral therapeutic to test the feasibility of CRISPR-based targeting of the UL56 gene. Specifically, we hypothesize that genetic ablation of UL56 expression will create an attenuated virus that will cause less viral shedding and milder disease. In the R21 proof-of-concept phase, we will develop tools for CRISPR-mediated disabling of the HSV-1/HSV- 2 UL56 gene. These will be tested in a vaginal infection mouse model. In the R33 further-validation phase, we will utilize the clinically relevant guinea pig model of genital herpes infection. We will further develop and test the efficacy of HSV-vector-based delivery of CRISPR gRNA targeting the UL56 gene. The effects on viral reservoir, shedding, and disease severity and frequency will be evaluated. The overall goal of these studies is to determine if CRISPR technology can be used to attenuate HSV in vivo and thereby prevent or reduce recurrent disease and viral shedding. This study will provide a basis for future development of potential therapeutical approaches focused on targeting UL56 for genital herpes infections.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Cellular polarity is a fundamental characteristic of all epithelial cells. Conserved polarity complexes include the apical domain of Crumbs/Pals1/Patj and Pard3/Par6/aPKC, and the basolateral domain of Scribble/Dlg/Lgl. The functional antagonism between these complexes is critical. Specifically, within the neuroepithelium, polarity complexes help orchestrate the appropriate lineage progression and subsequent neuron production of the cerebral cortex. Disruption to normal polarity processes or mutations in polarity genes contribute to a variety of human conditions. Mutations in Crumbs, Pals1, and Scribble, have been shown to cause ventriculomegaly, microcephaly, and seizures, respectively. Though many of the polarity complexes have been extensively studied in the context of neurodevelopment, the function of the basal polarity protein LGL1 (lethal giant larvae 1) is less understood. Loss of Lgl1 causes periventricular heterotopia (PH), or the abnormal accumulation of neurons along the ventricular surface. These current notions of LGL1 are derived from murine and drosophila studies, with no model of human cortical development to date. To address this, my work focuses on determine the function of Llgl1 in a human model of neurodevelopment using dorsal forebrain organoids (hCOs). We preliminarily have found that Llgl1 KO hCOs have abnormal development, including increased rosette size and reduction in rosette number. Ectopically located cells are also abundant within rosettes, suggestive of PH. Previous works have established a dependence on YAP signaling in the development of PH due to various genetic causes. Despite this association, no mechanistic studies exist describing how YAP is causing PH. We aim to address this gap in knowledge by elucidating the mechanism of YAP repression by Llgl1 in a human model. We hypothesize that LLGL1 directly represses YAP activation through modulation of kinase activity, and that the loss of this repression is what drives PH. To address this hypothesis we will start by determining the function of LLGL1 in hCOs through a KO hESC line. With this model we will perform immunostaining on markers of cerebral cortex development to characterize disruptions to neurodevelopment. I will also investigate the cause of increased rosette size, which we currently believe is due to an increase in proliferative division of neural progenitor cells. With single cell RNA sequencing I will also identify molecular and cellular changes through gene expression analysis. These studies will be followed up by a series of mechanistic studies that will identify the protein interactome of LLGL1 in neural progenitor cells, as well as elucidate the mechanism of YAP regulation by LLGL1. This work will provide novel insight into how apicobasal polarity regulates cortical development in a human model, as well as determine how YAP activation contributes to the development of PH.

NIH Research Projects · FY 2026 · 2026-05

MARCH6-ERAD in hepatic lipid metabolism and MASLD SUMMARY The liver plays a pivotal role in lipid metabolism, and its dysregulation is central to the progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), including steatosis, fibrosis, and nonalcoholic steatohepatitis (NASH). The endoplasmic reticulum (ER) maintains lipid homeostasis, with sterol regulatory element-binding protein 1 (SREBP1) acting as a critical ER-resident transcription factor. Elevated SREBP1 levels drive lipogenesis and hepatic steatosis in MASLD, underscoring the need for tight regulation. While SREBP1 degradation is essential for lipid homeostasis, the mechanisms governing its turnover remain poorly understood. ER-associated protein degradation (ERAD) plays a crucial role in maintaining protein homeostasis, targeting both misfolded and functional proteins for degradation. Among ERAD-specific E3 ubiquitin ligases, MARCH6 is underexplored in the liver, representing a significant gap in understanding hepatic metabolism. Preliminary studies reveal that MARCH6 functions as a sterol sensor, modulating lipid homeostasis through SREBP1 ubiquitination and degradation. Loss of MARCH6 in hepatocytes results in excessive lipid accumulation, increased expression of lipogenic genes, and exacerbated MASLD progression. This research proposes that MARCH6-ERAD serves as a critical negative regulator of lipogenesis, counterbalancing the positive regulation by HRD1-ERAD. To test the hypothesis that MARCH6-ERAD regulates hepatic lipid homeostasis via SREBP1 ubiquitination and degradation, this study proposes two specific aims: Determine the functional significance of MARCH6-ERAD in maintaining lipid homeostasis and its role in MASLD. This aim will explore the responsiveness of MARCH6 to metabolic signals, establish its role as a regulator of lipid synthesis and uptake, and assess its therapeutic potential in MASLD (Aim 1). Establish the role of MARCH6-ERAD in regulating lipid metabolism through SREBP1 ubiquitination and degradation. This aim will confirm SREBP1 as a substrate of MARCH6, delineate the ubiquitination-degradation mechanism, and assess its impact on MASLD (Aim 2). This study will provide groundbreaking insights into the post-translational regulation of hepatic lipid metabolism, positioning MARCH6-ERAD as a sterol sensor and a critical factor in preventing MASLD progression. RELEVANCE TO HUMAN HEALTH: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing global health concern linked to obesity and diabetes. This study investigates the role of MARCH6-ERAD as a critical regulator of hepatic lipid metabolism, demonstrating its ability to modulate SREBP1 degradation and maintain lipid homeostasis. By uncovering MARCH6's therapeutic potential, this research aims to inform novel strategies to prevent or treat MASLD and improve patient outcomes.

NIH Research Projects · FY 2026 · 2026-04

Summary In the event of a nuclear or radiological catastrophe, affected individuals are exposed to a wide range of radiation doses with the extent of injury depending on the victims' distance from the epicenter, the duration of exposure, and their inherent sensitivity/resistance to ionizing radiation, amongst other factors. While the use of Neupogen, Neulasta and Entolimod to treat hematopoietic acute radiation syndrome (H-ARS) has been approved by the FDA, therapeutic approaches to the treatment of radiation-induced vascular/endothelial injury are largely supportive. Vascular/endothelial injury is a leading cause of morbidity and mortality in radiation-induced injury through damage to vascular barrier function and increased leukocyte trafficking and there are no specific pharmacologic therapies available that protect from leukocyte- mediated tissue damage. While animal models have been used to develop therapeutics for treating radiation damage, use of emerging technologies such as organ-on-chip allows for testing of these therapeutics in biomimetic environments using primary human cells. We propose to integrate our microfluidic models of blood-brain barrier (BBB), gut, and lung into a multiorgan RadChip platform that incorporates essential features for testing radiation induced vascular injury. We will characterize the impact of radiation damage on vascular endothelial cell activation, barrier integrity, transendothelial electrical resistance (TEER) and interaction with immune cells in our RadChip composed of multiple important organ-specific cell types. The signaling pathways regulating radiation-induced vascular permeability and leukocyte migration in human EC will be determined. A novel in silico model will be used to elucidate cellular processes impacted by radiation exposure and identify/validate FDA-approved drugs/compounds as potential therapeutics for treating radiation injury. This multiorgan RadChip will be used to test the efficacy of FDA approved drugs for treating radiation induced vascular injury. The specific aims of this project are to 1) Use a multiorgan platform to model radiation-induced vascular injury in humans, 2) Determine the mechanism by which radiation injury impacts immune cell-endothelial cell interaction, 3) Use a novel in silico model to determine the signaling pathways regulating radiation-induced vascular damage to repurpose FDA approved therapeutics. These studies will not only provide important mechanistic insights into the underlying pathogenesis of acute radiation syndrome but also provide a platform to identify and screen potential FDA-approved drugs/compounds for treating radiation injury.

NIH Research Projects · FY 2026 · 2026-04

Abstract: It is well established that corticospinal tract (CST) axons have extensive axonal arborization throughout the brainstem and within spinal motor pools. How these CST terminals influence motor control through the brainstem in normal or lesioned animals remains unknown. Additionally, lesioning the CST within the pyramids or cervical spinal cord show deficits in skilled reaching. However, these CST lesions do not completely eliminate forelimb movements and locomotion remains intact, most likely mediated through rubrospinal, reticulospinal and propriospinal pathways. Whether or not these pathways require input from the CST to promote recovery has not been directly shown, only assumed through examination of CST sprouting into these nuclei. To better understand cortical control of brainstem motor nuclei, we have developed a novel genetic method to specifically lesion axons or their terminals while inducing minimal damage to the surround neurons or tracts. To induce a genetic lesion or pruning we have modified the human MAC-inhibitory protein CD59. This glycoprotein normally acts to protect cells from completement mediated lysis, however, intermedilysin (ILY) released by Streptococcus intermedius binds to the human but not rat form of CD59 to create a cytolytic pore. hCD59 expression in rodent models is a very effective mechanism to selectively ablate a variety of cells in vivo, even neurons, however, we found that it was poorly transported into axons. To increase penetrance into axons, we exchanged the endogenous GPI linkage with several know to be transported into axons. We engineered a novel hCD59 - thy1.1 GPI-linkage chimera showing excellent transport into axons and terminals and efficiently induced axonal severing in the presence of ILY. Here we hypothesize that this tool will be an effective method to dissect the motor control responsibilities of CST collaterals in extrapyramidal motor systems. There are 2 aims to the study. Aim 1 will examine the contribution of the regional distribution of CST after genetic lesioning of the CST axons in the cerebral peduncles, rostral pyramids, and cervical spinal cord. Aim 2 will examine the contribution of CST axonal terminals within specific brainstem nuclei known to be involved in mediating recovery after SCI. Outcome measure will include histological assessment of axon severing, immune response, gliosis and myelination at ILY injection site, as well as, behavioral assessment of skill forelimb use in normal and SCI rehabilitated rats. This technique could become a useful tool to examine the functional contribution of axonal collaterals and terminals within various motor or sensory nuclei.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Respiratory infections like the flu can lead to severe complications when bacteria invade the lungs, causing what is known as a super-infection. These infections significantly increase hospitalizations and deaths, particularly when caused by antibiotic-resistant bacteria such as Staphylococcus aureus (S. aureus). Despite medical advances, scientists do not fully understand why the immune system fails to prevent these severe infections after a viral illness. One major gap in knowledge is how mucosal immunity—the immune defense system of the lungs and airways—is disrupted following viral infections, making patients more vulnerable to bacterial super- infections. Our research focuses on a group of molecules called eicosanoids, which regulate inflammation and immune responses in the lungs. Specifically, we are studying how a subset of these molecules, called cytochrome P450 (CYP450)-derived lipids, influence immune cell behavior during bacterial super-infections. Our preliminary findings suggest that CYP450 lipids activate a protein called PPARα, which weakens the immune system's ability to fight bacteria and disrupts mucosal immunity. Mice lacking PPARα showed improved resistance to super-infections, suggesting that blocking this pathway could enhance bacterial clearance and restore lung immune defenses. Additionally, we used advanced imaging techniques to track these lipids in lung tissues and found that their distribution is linked to areas of severe infection. However, we still do not fully understand how these lipids influence immune cells at a molecular level or how they alter mucosal immunity to create conditions favorable for bacterial persistence. To address these gaps, we will use two cutting-edge approaches: 1) spatial transcriptomics, which allows us to see how different cells in the lung respond to infection at a single-cell level, and 2) a lung-on-a-chip device, which mimics human lung tissue to study real-time interactions between immune cells and bacteria. These approaches will help us understand how CYP450 lipids and PPARα signaling contribute to immune dysfunction and mucosal immunity breakdown. By uncovering the molecular mechanisms behind immune suppression and mucosal immune dysregulation during bacterial super-infection, our research has the potential to lead to new treatments. Targeting PPARα could offer a novel strategy to enhance the immune response, improve mucosal immunity, and reduce the severity of respiratory infections. This study will provide critical insights into how the body responds to lung infections and may inform future drug development to combat antibiotic-resistant bacteria.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY Recurrent caries is the leading cause of dental restoration failure, costing the U.S. over $5 billion annually. Enhancing the seal of dental materials bonded to hard tissues is critical for preventing recurrent caries, disease progression, and tooth loss. Eliminating bacteria at the restoration margins can prevent the biochemical degradation of these materials to deter seal damage and thus extending the clinical lifespan of restorations. We have developed a novel antibacterial composites and adhesives with piezoelectric properties. Piezoelectric biomaterials have proven antimicrobial effects. This innovative approach significantly improves upon current technologies by using a single filler that provides long-lasting antibacterial effects without antibiotic resistance issues. Sound or acoustic waves (such as the human voice) can stimulate piezo- adhesives to produce the necessary electrical charges to elicit antimicrobial effects that prevent bond degradation and extend the durability of dental restorations. In this study, we propose to investigate how the properties of the human voice (such as pitch, intensity in dB, duration, angulation) influence charge production and antimicrobial effects in restorations (aim 1). Additionally, this project will assess the degradation of the tooth-restoration interface under representative oral conditions and with piezo-adhesives stimulated by the human voice and mastication forces. This research will provide crucial insights into how smart adhesives can improve the durability of dental composite restorations.

NIH Research Projects · FY 2025 · 2025-09

Abstract Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection with over 1.7 million cases/year and >350,000 deaths in the US. Neutrophils are important contributors to the dysregulated immune response and play a critical role in sepsis-induced organ failure through interactions with the vascular endothelium resulting in barrier disruption and increased neutrophil trafficking into vital organs. While neutrophils are vital to host defense, neutrophil dysregulation has a critical role in organ damage through release of proteases, neutrophil extracellular traps (NETs), and reactive oxygen species (ROS), which damage host tissue leading to organ failure. Drug development has been hindered for multiple reasons including the heterogenous nature of sepsis. There is now a consensus that the host response to sepsis is highly diverse among patients, and this heterogeneity impacts immune function and response to infection. To develop more effective and targeted therapeutics, a better understanding of neutrophil characteristics and identification of distinct neutrophil subpopulations is needed. To our knowledge, no studies have examined the impact of different neutrophil phenotypes on the functional consequences of neutrophil-endothelial interactions in sepsis or linked these functional consequences to altered omics. We hypothesize that functional neutrophil phenotypes in sepsis patients regulate their ability to interact with the vascular endothelium and traffic into critical organs. Employing organ-on- chip analysis, we identified three neutrophil functional phenotypes (Hyperimmune, Hypoimmune and Hybrid) in sepsis patients based on ex vivo neutrophil adherence/migration patterns. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group had increased oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. We will use a synergistic combination of our organ-on-chip, clinical data, proteomics, and in silico modeling to provide important mechanistic insight into neutrophil functional phenotypes in sepsis. The aims of this study are: 1) Characterize the temporal progression of neutrophil functional phenotypes in patients to ascertain whether neutrophil functional phenotypes shift as sepsis progresses, 2) Test the hypothesis that neutrophil functional phenotypes are organ specific in their interactions with different organ-specific endothelial cells, 3) Determine the impact of sepsis patient phenotypes on response to therapeutics. We will identify FDA-approved drugs that target differentially expressed proteins within and across phenotypes. Using human patient neutrophils offers a unique platform to identify omic and phenotypic differences in drug responses between neutrophil phenotypes. The proposed studies will determine the impact of neutrophil phenotypes on therapeutic responses.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The lysosome is emerging as a key regulatory hub within the cell, crucial for maintaining homeostasis and viability under stress. This acidic, degradative organelle not only supports metabolic adaptation through mitophagy and autophagic clearance but also plays a crucial role in fine-tuning local signaling events via controlled ion release. While thus far lysosomal ionic regulation has proven to be vital for cardiac homeostasis, its alteration in disease states remains largely unexplored. Our recent findings reveal that the calcium/proton-permeable two-pore channel (TPC2) is one of the most significantly altered lysosomal ion channels in cardiac disease, with marked upregulation following acute injury that persists throughout heart failure progression. Replication of this upregulation in vitro and in vivo demonstrates its pathogenic role, with elevated TPC2 activity linked to increased cardiomyocyte death, exacerbated ischemia/reperfusion injury, and progressive cardiac dysfunction. Mechanistic studies suggest that TPC2-mediated cell death is likely driven by lysosomal calcium-induced mitochondrial calcium overload and subsequent permeability transition pore (mPTP) opening. Additionally, proton efflux from hyperactive TPC2 appears to impair lysosomal acidification and autophagic clearance, further diminishing ischemic stress adaptation. Accordingly, the proposed research will test the hypothesis that excessive lysosomal TPC2 ion release significantly contributes to MI pathogenesis by promoting cardiomyocyte death and weakened cellular resilience. We will address this hypothesis in two specific aims: In Aim 1 we will employ in vitro and in vivo genetic manipulations to determine whether sustained increases in TPC2 activity drive ischemic pathological cardiac remodeling and decompensation, and therapeutically test if TPC2-selective inhibition can prevent HF development In Aim 2 we will leverage our range of lysosomal-targeted biosensors, molecular tools, and TPC2 gain- and loss-of-function models to explore how lysosomal calcium and proton efflux independently influence cardiomyocyte resilience and survival, and additionally test whether TPC2-dependent changes in post-MI remodeling preferentially favor one ionic pathway over the other. The outcomes of this research will provide transformative insights into lysosomal ion regulation, stress adaptation, and cell survival, paving the way for novel strategies to combat ischemic heart disease.

NIH Research Projects · FY 2025 · 2025-09

By conventional criteria, nearly all deaf and hard-of-hearing (DHH) children qualify as late talkers, but for different reasons than hearing children. For DHH children, delayed development of a first language (whether spoken or signed) is typically the result of reduced access to linguistic input, which in turn depends on a range of parental decisions and practices, such as the selection and use of appropriate and effective hearing technologies and the language and communication practices used in the child's environment. Parents typically work with professionals in making these decisions, but these professionals typically have limited training and experience supporting language acquisition in DHH children. There is universal agreement that parents should receive comprehensive and unbiased information to support them in these decisions, but at present there is no further guidance about exactly what information they need. Furthermore, after identifying the relevant set of information that should be given to families, we should ideally have a way to evaluate the extent to which parents (and professionals) accurately understand that information. Only then can we be confident that parents are making truly informed decisions. Our Pennsylvania-based team responds to these needs by first talking with inexperienced parents and professionals who are currently attempting to support language acquisition in DHH children, to find out what they want to know. In addition, we talk with experts across the state of Pennsylvania to determine what the experts think that these novices need to know. With support from an Advisory Board that includes diverse professional and lived experience, we identify the information needs that are most prominent and relevant to most children: these will form the core of a resource that allows parents (and professionals) to objectively self-evaluate their understanding of this key information. Because some (though not all) informational claims may be disputed, we conduct a Delphi study with these experts plus an additional group of researchers to identify where there is consensus vs. dispute. We include both types of items in the resource, under the view that users should understand which claims are and are not controversial. Because this is a new approach, we will return to the inexperienced parents and professionals from earlier in the study to get their feedback on the prototype. As a result of this work, we will learn what parents and professionals want to know and what they need to know about supporting language acquisition in DHH children: most of whom qualify as late talkers. We will identify where experts agree and disagree, and we will develop a resource that gauges the extent to which parents and professionals understand what they need to understand in order to make well-informed decisions about supporting the DHH child's language acquisition.

NIH Research Projects · FY 2025 · 2025-09

Project summary: Neuropsychiatric Lupus (NPSLE) is a common but under-researched aspect of systemic lupus erythematosus (SLE). Symptoms include anxiety, depression, and cognitive impairment. NPSLE severity varies, indicating a complex pathogenesis. Excessive Type I interferon (IFN) production and response is a hallmark of SLE. High IFNα levels correlate with depression and anxiety in lupus patients and mice. Targeting theType I IFN response is a therapeutic goal. The FDA has approved anifrolumab, an anti-IFN receptor antibody, for moderate to severe lupus; however, its efficacy in NPSLE remains untested. IFNAR blocking in pre-clinical models has shown varied outcomes, suggesting complex IFN regulation in different lupus models and highlighting the need for alternative IFN suppression pathways. Our research discovered that the kallikrein-kinin system (KKS) can suppress Type I IFN response, introducing a new pathway for IFN suppression. KKS regulates many physiological processes, including inflammation and brain functions. KKS components, including kallikreins and bradykinins, along with ACE inhibitors (ACEi), suppress IFN responses in lupus models. Administering the ACEi captopril in lupus mice reduced IFN gene expression, neuroinflammation, and depressive behavior. Exogenous kallikrein-1 (klk1) also improved depressive behavior and reduced IFNα levels in lupus mice. NPSLE symptoms appear early in lupus, indicating a role of peripheral autoimmunity. Brain-reactive antibodies, cytokines, and inflammation contribute to NPSLE pathogenesis. Extracellular vesicles (EVs) from SLE patients carry inflammatory cargo and may influence NPSLE. High levels of cell-free DNA (cf-DNA) is found in SLE patients and the importance of cf-DNA as a biomarker and immune mediator is researched extensively. Reducing peripheral IFNα could reduce CNS inflammation and improve symptoms. We hypothesize that excessive peripheral IFNα, production and response, causes NPSLE. Reducing IFN responses with ACEi and klks will decrease CNS inflammation and behavioral symptoms. In aim 1, we will dissect the cellular and molecular mechanisms by which the KKS and ACEi modulate IFN pathways. Using DC and microglia as cell models, we will analyze these mechanisms in the periphery and brain, respectively, in established NPSLE models (MRL/lpr and NZBW/F1), and in the new microglia specific IFNAR-knockout B6/lpr model. We will correlate these molecular mechanisms with behavioral outcomes. In aim 2, we will analyze the pathways by which peripheral immune responses affect neuroinflammation and behavior in the models in Aim 1. We will focus on the effects of circulating peripheral components (EVs and cf-DNA) from mouse and human cells on brain cells (primary mouse cells or human cell-lines). We will also analyze parallels in IFN-KKS related gene/protein profiles in EVs from lupus patients’ samples (SLE and NPSLE). These studies aim to (1) elucidate the therapeutic potential of KKS molecules in SLE and NPSLE, (2) understand the mechanisms of ACE inhibitors, (3) identify and validate novel peripheral biomarkers for NPSLE prognosis, and (4) provide insights into peripheral-brain interactions in chronic inflammation.

NIH Research Projects · FY 2025 · 2025-09

Project Summary With a 5-year survival rate of <20% and substantial lack of response to the current standard of care, esophageal squamous cell carcinoma (ESCC) is among the deadliest malignancies worldwide. Notably, patients with the food-allergen-mediated inflammatory disease eosinophilic esophagitis (EoE) fail to develop esophageal cancer according to recent epidemiological studies. Our own publication recently used mouse models of EoE and ESCC to demonstrated that EoE limits carcinogenesis in vivo. Based on our own published and preliminary data, we hypothesize that EoE activates anti-tumor responses in the esophagus to limit ESCC carcinogenesis. We will test this hypothesis by: Determining the functional role of senescence in EoE-mediated suppression of ESCC (Aim 1); determining the impact of IL-13 on esophageal epithelial cell fate (Aim 2); and defining the direct impact of EoE upon the cellular landscape of ESCC esophageal mucosa and associated inflammatory cells (Aim 3). These studies provide the first investigation of the direct mechanisms through which EoE can suppress esophageal carcinogenesis. Ultimately, we aim to leverage these mechanisms to develop novel approaches for prevention and therapy of ESCC. As allergic inflammation has been reported to be negatively associated with various types of cancer, our findings may have significant implications in the field of cancer biology field. The work outlined in this application will further provide the PI with a comprehensive scientific research experience encompassing discovery and subsequent target validation in the field of cancer biology. The research component of the proposal coupled with the detailed training plan will support the PI as she pursues her goal of becoming an independent investigator at a top academic research institution.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Metabolism is the chemical necessity of all living things, allowing the use and interconversion of nutrients for biomass and energy. A fundamental characteristic of eukaryotic metabolism is the compartmentalization of metabolic pathways within and between subcellular compartments (especially mitochondria, cytoplasm, and potentially within the nuclear compartment). This allows the simultaneous existence of competing reactions, underpins regulatory control of major metabolic pathways, and allows metabolites to function as signaling molecules. Acyl-coenzyme A thioesters (acyl-CoAs) are evolutionarily conserved critical cofactors that are made and used in distinct parts of the eukaryotic cell. In different sub-cellular compartments, acyl-CoAs can be used to meet energy needs, act as signaling molecules, and serve as acyl-donors for post-translational modifications (PTMs) of proteins. Our current work has demonstrated that we can measure the compartmentalized pools of major acyl-CoAs and identified specific fates of localized pools. In this proposal we will 1) examine the sources, fates, and effects of pool specific modulation of cofactor metabolism. Simultaneously, we will 2) push the limits of sensitivity to single cell metabolomics and test the generalizability of our approaches to other metabolites. Under the aegis of a MIRA we will have the freedom to innovate and pursue these major research directions in their most important technical and biological directions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Primary prevention and treatment for CVD risk factors, particularly hypertension, diabetes, and hyperlipidemia, are crucial in the comprehensive management and CVD risk reduction among persons living with HIV (PLWH). Clinical pharmacists and their involvement in HIV care through comprehensive medication management lead to improved medication adherence, evaluation integrated viral load suppression, and retention in are among PLWH. of the clinica l effectiveness, economic impact, and scalability of pharmacist-led interventions in HIV and CVD care in SSA are still understudied. c However, The overall objective of this proposal is to evaluate the effectiveness and cost-effectiveness of a multi-component implementation strategy to prevent and manage cardiovascular disease in PLWH. Our central hypothesis is that a pharmacist-led intervention (INTEGRATE-RX) which includes – (1) integration of clinical pharmacists for CVD medication initiation and maintenance, (2) pharmacist-coordinated access to CVD essential medicines, and (3) pharmacist-coordinated peer support for medication delivery and psychosocial counseling – will be clinically effective and cost-effective in improving CVD outcomes amongst PLWH. In Aim 1, we will design a pharmacist-led HIV/CVD integrated care implementation strategy in western Kenya. Using a human-centered design approach, we will refine a pharmacist-led multicomponent cardiovascular risk reduction intervention to enhance HIV/CVD care. We will evaluate the acceptability and appropriateness of the implementation strategy amongst patients, pharmacists, physicians, other providers, peers, and administrators. In Aim 2, we will evaluate the clinical effectiveness by conducting an implementation hybrid type 2 stepped-wedge clustered randomized controlled trial comparing: INTEGRATE-Rx implementation strategy and usual care. The primary clinical outcome will be one- year change in SBP. The primary adherence outcome will be medication adherence. The primary implementation outcome will be fidelity. Secondary outcomes will include change in viral load, low-density lipoprotein (LDL), patient-reported quality of life, and RE-AIM metrics. In Aim 3, we will estimate the cost-effectiveness and budget impact of INTEGRATE Rx in terms of cost per patient with controlled hypertension and per disability-adjusted life year (DALY) saved. To assess the financial impact of adopting this high-value intervention, we will estimate the incremental cost per unit reduction in SBP and per DALY saved, compared to usual care. We will model the budget impact of increasing intervention coverage to 50% of the eligible population by 2030 to promote wider county-level adoption. The research will be conducted by a transdisciplinary team with diverse and complementary expertise. Data generated from our study will provide important policy guidance for President'sEmergency Plan for AIDS Relief (PEPFAR)supported countries trying to address the growing burden of ASCVD amongst the adult and aging population with HIV and will provide rigorous evidence on the roles of clinical pharmacists in chronic disease management in sub-Saharan Africa.

NIH Research Projects · FY 2025 · 2025-08

PROJECTSUMMARY/ABSTRACT Individuals with schizophrenia spectrum disorders experience a range of symptoms that cause high levels of functional impairment, thus representing a large personal and public health burden. Therefore, studies evaluating early psychosis can help to uncover how symptoms of schizophrenia first arise and elucidate more effective avenues for early intervention. Of particular importance is the examination of negative symptoms (NS), such as avolition, anhedonia, asociality, and expressive deficits, as they tend to present prior to the onset of positive symptoms, are more resistant to treatment, and are more strongly predictive of functional outcomes. Mounting evidence suggests that the cerebellum (Cb) is involved in diseases of disordered socio-affective and volitional functioning. Further, preliminary findings from stimulation of the Cb midline have shown promise for mitigating NS in schizophrenia. Despite these converging lines of research, no one, to date, has examined Cb-VTA connectivity as being a critical substrate in the pathophysiology of specific NS in psychosis. Therefore, the proposed study will examine the association between structural and functional Cb-VTA connectivity and aberrant goal-directed, hedonic, social, and expressive functioning. The proposed study will use data from the Human Connectome Project for Early Psychosis to study first early 16-35-year-olds who represent both affective and non-affective psychosis manifestation. Via clinical interviews, resting state functional magnetic resonance imaging (rsfMRI), and diffusion-weighted imaging scans, I will take a multi-modal, computational approach to understanding Cb contributions to NS in psychosis. Specifically, I will reconstruct the Cb-VTA tract across sagittal segments of the Cb cortex, and probe for dissociable contributions to distinct NS based on hierarchical Cb seed regions and examine differences in tract micro- and macrostructure between early psychosis patients and healthy controls. Next, I will assess for physio-physiological interactions and effective connectivity profiles between the Cb, VTA and higher-order structures such as the dorsolateral, orbitofrontal, and premotor cortices, plus the ventral striatum, and amygdala to assess how the Cb-VTA substrate may contribute to perturbations upstream in the context of distinct NS. Findings from the proposed study have the capacity to provide additional insight into previously established frontal and reward-related alterations associated with NS, thus providing a novel framework for understanding the relations between the Cb, frontal lobe, reward mechanisms and NS. Further, we will explore potential differences in the association between various structural segments of the Cb- VTA white matter tract and NS across first-episode and control individuals to assess specificity. To complete this study, a training plan has been developed that consists of formal coursework, workshops, technical development, and mentorship. This fellowship would allow me to obtain additional training opportunities that would not otherwise be available to me, so that I may cultivate expertise on functional neuroimaging, reward, Cb functional anatomy, and psychosis necessary to become an independent cognitive neuroscientist.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract: This proposal describes a research plan for Zhengjie Zhou, Ph.D., for the R00 portion of the NIH mentored career award (K99/R00). The PI is completing training in an NIH K99 fellowship (K99HL166870) and is trained in vascular biology, lung biology, molecular biology, and bioengineering. This proposal tests the overall hypothesis of formulating novel lung-targeting nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection. Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of endothelial cells (ECs), epithelial cells, and the following uncontrolled cytokine storm. Based on our recent research about a vascular cell adhesion molecule-1 (VCAM1) targeting nanotherapeutic study, I rationally designed and optimized a targeting lipid nanoparticle (LNP) that enables robust mRNA delivery in vivo in a cell-specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate epithelial cells innate immune pathway by epithelium specific delivery of 2’-5’-oligoadenylate synthetase 1 (OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting LNP targeted the inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1. Our preliminary data demonstrated that the OAS1 mRNA/epithelium-targeting LNP targeted the mice inflamed lung epithelium and significantly reduced the H1N1 replication and lung ARDS. Aim 1 will comprehensively evaluate the therapeutic potency of VCAM1-targeting LNP to restore endothelial KLF2 and lessen ARDS in a clinically relevant rat ARDS model induced by high-tidal ventilation (HTV). Aim 2 will determine how epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice by OAS1 mRNA/epithelium-targeting LNP, and will determine its therapeutic effect to treat respiratory virus-induced ARDS. Successful completion of these projects will provide a promising mRNA therapeutic treating lung disease and provide an “effective responder” in viral pandemics, regardless of virus evolution and mutation. This mRNA delivery platform is adaptable and potentially beneficial for various cardiovascular diseases.

NIH Research Projects · FY 2025 · 2025-08

Abstract: Almost 50% of people living with HIV-1 (PLWH) under combination antiretroviral therapy (cART) still show milder forms of HIV-1 associated neurocognitive disorders (HAND). HAND shows the main molecular hallmarks of Alzheimer's disease (AD), including dysregulation of function and expression of amyloid precursor protein (APP), β-secretase and presenilin-1 (PSEN-1). HIV-1 promotes chronic neuroinflammatory microenvironments through latent activation in aging PLWH, and Aβ formation has also been observed in an age-dependent manner. However, the cause of HAND progression in PLWH and the role of HIV in Aβ formation are not truly understood. Recent studies have considered the accumulation of Aβ as result of a viral escape strategy adopted by HIV-1 in microglial cells in the brain. It has been also described that alternative splicing of APP results in generation of circular RNAs (circRNA), essential members of so-called competing endogenous RNA networks (or ceRNA, circRNA/microRNA/mRNA) involved in regulating gene expression. CircRNAs are generated by back-splicing and can bind multiple microRNAs and inhibit their function, acting as microRNA sponges, or can be translated into protein. Two circRNAs, the circ_0007556 which is derived from the APP gene, and the circ_0004381, have been recently described in association with AD. Interestingly, it has been recently demonstrated that circ_0007556 could be an alternative template for Aβ peptide translation. Moreover, inhibition of circ_0004381 improved the cognitive function via miR-647/PSEN1 axis in a murine AD model. Our preliminary data from HIV-1 infected human cerebral organoids (hCOs) suggest that expression of circ_0007556 is upregulated in HIV-1 infected organoids independently from cART treatment. In addition, we found that the circ_0004381 is downregulated by HIV-1 in hCOs and its expression is rescued by cART. Based on our preliminary data, we hypothesized that circ_0007556 and circ_0004381 may be involved in the Aβ accumulation induced by HIV-1, and HIV-1 infection may dysregulate the events involved in generation of Aβ to sustain the productive release of infectious viral particles. Therefore, we propose that the modulation of these circRNAs may provide mechanistic and functional data on the involvement of Aβ accumulation in HIV-1 infected brain and be an elective new target for the development of novel therapeutic interventions.

NIH Research Projects · FY 2025 · 2025-08

Primary somatosensory axons of the dorsal root (DR axons) relay sensory information of diverse modalities from the periphery to the spinal cord (SC). They are commonly damaged by DR injuries, which cause permanent loss of sensation and coordinated limb movements. The devastating consequences occur because DR axons stop regeneration at the entrance of the SC, the dorsal root entry zone (DREZ), and because there is no therapy that restores sensory connections even for nociception, which does not require long-distance axon regeneration past the DREZ. Importantly, increasing evidences strongly suggest that DR axons prematurely terminate regeneration at the DREZ by forming synapses with oligodendrocyte precursor cells (OPCs). This novel inhibitory mechanism, which we termed ‘synaptic arrest’ by OPCs, raises the intriguing possibility that OPCs act as the major mechanism restricting regeneration not only at the DREZ but also intraspinal regeneration of DR axons, broadly elsewhere in the SC. Furthermore, synapse formation with OPCs may also restrict appropriate synapse formation of sensory axons with correct SC neurons, further hampering modality-specific reinnervation and functional recovery. In this proposal, we will address these clinically significant issues while investigating novel therapeutically applicable strategies to overcome synaptic arrest. In addition, we will use advanced imaging and mouse genetic tools that now permit selective investigations of physiologically distinct DR axons of specific modalities. Aim 1 will determine if specific axon subtypes terminate regeneration primarily by OPC-mediated synaptic arrest at the DREZ. Aim 2 will determine if BRAF/mTOR viral activation of specific axon subtypes overcomes synaptic arrest, enabling modality-specific functional regeneration in the SC. Aim 3 will determine if transient OPC ablation markedly enhances BRAF/mTOR-elicited intraspinal regeneration and/or reinnervation, robustly enhancing modality-specific functional recovery. Multifaceted information gained from these studies will fill significant gaps in current knowledge, moving the field substantially forward. Together with the unprecedented modality-specific investigations, this information could be very useful for developing new clinical therapies to restore specific somatosensory functions after debilitating DR injuries.

NIH Research Projects · FY 2025 · 2025-08

Abstract Oral health disparities in the United States are a significant public health issue, particularly among underserved populations, including Hispanics, non-Hispanic Blacks (NHB), and rural non-Hispanic Whites (NHW). Poor oral health not only leads to oral diseases but is also closely linked to systemic conditions such as diabetes, cardiovascular disease, and oral cancer (OC). Hispanics and NHBs are twice as likely to be diagnosed with late- stage OC, resulting in survival rates below 40%, compared to over 80% for non-Hispanic Whites. This highlights the urgent need for integrated healthcare that connects oral and general health to improve outcomes for these vulnerable groups. Despite efforts to integrate medical and dental care, oral healthcare remains largely disconnected from the broader healthcare system. The proposed study aims to connect oral health with systematic health to better integrate medical and dental care by developing linked databases, creating real-time clinical tools to improve oral clinical care, and identifying individuals at elevated risk for OC using fair and responsible artificial intelligence (AI) methods. We will leverage existing electronic health records (EHR) and electronic dental records (EDR) from three major dental institutes [Temple University School of Dentistry (TU), University of Colorado School of Dentistry (UC), and West Virginia University School of Dentistry (WVU)] that serve underserved populations to develop and implement clinical tools that may facilitate dental practice and reduce oral health disparities related to OC. The four aims are: (1) develop real-world AI-ready datasets to understand and reduce oral health disparities; (2) create a clinical tool that provides real-time medical history, lab values, and medication information to dental providers; (3) predict OC risk using federated learning across multiple institutions with responsible and interpretable AI methods; and (4) explore the feasibility of implementing the clinical tool and AI prediction model at Temple University. This multi-site initiative addresses a critical gap in healthcare delivery for underserved populations by integrating medical & dental care. It has the potential to reduce oral health disparities by ensuring early OC diagnosis and access to up-to-date patient information from dental providers. The clinical tools and OC prediction risk tailored to diverse populations have the potential to detect early OC diagnosis and treatment, leading to improved OC prognosis and OC outcomes aligning with NIDCR's strategic priorities and setting a new standard for reducing health disparities and advancing precision dental care.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Description. Our goal is to study the feasibility of a newer, potentially safer and better nanocarrier design for enhancing the delivery of a variety of therapeutic agents to bacterial biofilms. Biofilms are the main culprit causing the majority of chronic wounds. Once established, biofilms can protect the encased bacteria against immune system and most antibiotics, thus rendering the biofilm-associated infections very difficult to treat. Despite the advance of antibiotics and development of new anti-biofilm agents, the first and foremost challenge remains to be delivering enough drugs into the biofilms. This is a realistic need as much higher drug concentrations are needed for effective treatment of the bacteria in biofilms than in their planktonic state. Considering that many mature biofilms produce a microenvironment more acidic than the surrounding host tissues, in this application we propose to exploit this biofilm characteristic by developing a new hybrid nanocarrier design with a poly(lactic-co-glycolic acid) (PLGA) core coated with pH-responsive, ionizable lipids. We hypothesize that: (1) by decorating PLGA with ionizable lipids that turn cationic in an acidic microenvironment, the resulting “hybrid” nanocarrier will be well-retained in a biofilm, yet stay nearly neutral outside to avoid excessive binding to the negatively charged host cell surfaces, and (2) with the lipid coating, the PLGA core will still preserve its proven capability to encapsulate a wide range of different drugs. Moreover, this nanocarrier may also have enhanced interaction with the negatively charged bacteria cell surface. Driven by these hypotheses, the following aims are developed: (1) Develop efficient, stable ionizable hybrid nanocarriers capable of entrapping diverse therapeutic agents for anti-biofilm therapy. (2) Verify and optimize the impact of decorating nanocarriers with pH-responsive, ionizable lipids on their distribution and retention in biofilms. (3) Evaluate the feasibility to enhance anti-biofilm activities of antibiotics and quorum sensing inhibitors with pH-responsive, ionizable hybrid nanocarriers. Relevance to Public Health. Biofilms are nearly ubiquitous and can form on the surfaces of most medical devices and host tissues, resulting in a high incidence of device-related infections and tissue-related infections. They are a critical barrier against effective drug treatment of many chronic infections such as delayed wound healing, cystic fibrosis, endocarditis, urinary tract infections, etc, and are also responsible for bacteria dissemination through the biofilm dispersal mechanism, as well as promoting other diseases including cancer. However, up to date there is no drug officially approved for biofilm eradication. Successful completion of this project will validate the feasibility of a new nanotherapy that can increase the selectivity of antibiotics and antibiofilm compounds for biofilms, prolong their retention there and avoid excessive distribution to the host tissues. Consequently, the effectiveness and safety of biofilm therapy can be significantly enhanced.

NIH Research Projects · FY 2025 · 2025-08

Abstract Postinflammatory hyperpigmentation (PIH) disorder is a condition in which pigmentation is abnormally increased (hypermelanosis) in skin areas that are affected by cutaneous inflammation or injury. PIH can arise in individuals of all skin types, but particularly and most frequently affects individuals with skin of color with Fitzpatrick type III and higher skin types, including Africans, African Americans, Hispanics/Latinos, Asians, Native Americans, Pacific Islanders, and those of Middle Eastern descent. In fact, PIH is the most common pigmentary disorder in patients with skin of color. PIH can have devastating psychological and quality-of-life-associated effects on the patients. Despite being so common, PIH remains severely understudied and its molecular mechanisms remain largely elusive. PIH is a response of skin to cutaneous inflammatory stimulations such as allergic contact dermatitis, acne and skin wounding. At the inflamed and wounded sites, the hyperpigmentation is due to an increased production and secretion of melanin pigment by melanocytes and can last for months to years, or even permanently. The current treatment options have limited efficacy, and can have undesirable side effects upon usage for longer periods. Consequently, the need for new and safer treatment options remains as dire as ever. Prevention of PIH is considered as the primary and the most valuable option; however, complex unknown pathogenesis of PIH contributes to the current lack of prevention strategies. Skin inflammation process recruits robust cytokine-secreting inflammatory cells that secrete interferon-gamma (IFNG) cytokine into the skin microenvironment, which then orchestrates the inflammatory processes. For example, IFNG plays an important role in wound healing process. Our preliminary studies suggest that IFNG induces melanin synthesis in melanocytic cells. In this proposal, we will study IFNG signaling pathway as a novel instigator of PIH and a viable target for prevention and treatment strategy for PIH. We propose two aims. In Aim 1, we will elucidate the molecular mechanisms of IFNG-mediated melanogenesis, including the role of IFNG-induced hyperglycosylation of Tyrosinase and melanosomal alkalization in inducing melanogenesis. In Aim 2, we will determine whether IFNG mediates PIH using novel in vivo mouse models. We will develop novel mouse models of PIH by utilizing chemically induced inflammation and wound-healing assays using the SKH2/J hairless and ARE-Del-/- (chronic IFNG producing) mice. We will then ask whether genetic ablation of IFNG signaling in melanocytes inhibits PIH. Finally, we will perform proof-of-principle preclinical studies to test whether inhibition of IFNG signaling can block PIH.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT The overall goal of this R03 award is to provide Gabriella McLoughlin, PhD, MS, with funding to investigate the impact of an equity-focused implementation strategy on participation and uptake of Universal School Meals (USM) among the students most at risk for food insecurity and obesity, building on her current K01 award. Childhood food insecurity and obesity inequities have been exacerbated in recent decades, such that children from racial and ethnic minority and low-income backgrounds are most at risk, increasing the marginalization they face and unequal opportunities to accessing healthy and affordable foods. Multiple factors, such as increased food insecurity resulting in a low-quality diet, contribute to this increased threat. Since children and adolescents consume over half of their energy intake at school, providing free nutrient-rich breakfast and lunch to low-income youth through Universal School Meals (USM) is a key policy approach to addressing obesity inequities. Adoption of USM is linked with reductions in obesity risk for low-income students, improved diet quality, reduced food insecurity, and enhanced academic achievement. Unfortunately, evaluation of USM so far has focused mainly on school-level aggregate outcomes, potentially masking inequities in participation among students most at risk for food insecurity and obesity. Thus, the purpose of this R03 award is to investigate whether an equity-focused implementation strategy improves uptake of USM among students who are most at risk for food insecurity and obesity through a multi-method approach. The proposal builds on the PI's existing K01 project which aims to develop, implement, and test a novel implementation strategy to improve the impact of USM through a combined implementation and effectiveness cluster randomized trial. The goals of this R03 will be achieved through two aims: 1) Determine whether equity-focused implementation of USM leads to increased uptake of meals by students at high risk of food insecurity and obesity, and 2) Assess perceived acceptability and sustainability of equity-focused USM among students at high risk of food insecurity and obesity. This evaluation will require merging several student-level datasets: meal participation (primary outcome variable), food security, body mass index (BMI), demographic indicators (e.g., race, ethnicity, income status), attendance, and dietary intake to create a food insecurity and obesity risk index and run multi- level regression models to evaluate change in uptake among low, moderate, and high-risk participants. Aim 2 will require collecting qualitative interview data among students at varying risk for food insecurity and obesity on perceptions of equity-focused implementation. This work will enhance the impact of the PI's existing K01 by adding innovative student-level analyses, which will provide robust evidence on the impact of USM on socially and economically marginalized populations. This R03 award holds significant potential for public health impact and will provide preliminary data for Dr. McLoughlin to apply for a R01 award to test the resulting equity- focused implementation strategy in a larger cluster randomized implementation and effectiveness trial.