Cincinnati Childrens Hosp Med Ctr

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT Antiretroviral therapy (ART) is remarkably successful at preventing AIDS but is unable to cure HIV infection due to a durable pool of latently infected cells carrying integrated HIV provirus. The persistence of this latent reservoir contributes to a growing population of people living with HIV whose lifespans are shortened by non-AIDS co- morbidities of chronic infection and in whom HIV infection can reactivate upon ART interruption. Selective targeting of the latent HIV reservoir is difficult due to the absence of either detectable viral antigens or cell- surface markers that would reveal viral reservoirs to the immune system. Alternative strategies to reactive latent HIV in these cells and promote susceptibility to immune attack are not sufficiently robust to facilitate elimination of an adequate quantity of the reservoir to achieve cure. Latent provirus in ART-treated HIV-1-infected patients highly enriched in a heterogeneous pool of CD4 T cells exhibiting variably elevated expression of sets of cell surface proteins, including programmed cell death-1 (PD-1) and very late antigen-4 (VLA-4). We believe that logic-gated chimeric antigen receptors (CAR) can be developed to facilitate highly selective killing of cells with these combination of markers (AND gate targeting of cells co-expressing PD-1 and VLA-4, for example) while sparing important uninfected immune effector cells with the similar features (NOT gate to prevent killing of CD8+ T cells). This strategy would permit virus-agnostic eradication of sets of cells with defined phenotypic features that encompass most latently infected cells. Such a strategy could be employed in the context of effective ART to shrink the viral reservoir to a level that can be restrained by antiviral immune responses to facilitate drug-free remission. In this proposal, we will build these CAR molecules and test their ability to durably endow human NK cells with highly selective functional activity against discrete subsets of T cells. In addition, we will characterize the expression of the targeted combination of receptors on latently infected tissue T cells. These studies will provide compelling evidence of the feasibility of these logic-controlled CAR regimens and validate a set of target markers in a pre-clinical latency model. These data will facilitate more advanced preclinical testing in non-human primates, humanized mice, and bona fide reservoir cells from people living with HIV.

NIH Research Projects · FY 2026 · 2026-06

Project Summary In this proposal, we address a critical gap in our understanding of adipose tissue biology and energy metabolism, with a focus on the role of beige adipocytes in whole-body energy expenditure. Despite extensive research linking the beiging of subcutaneous white adipose tissue (scWAT) to increased energy expenditure and improved metabolic health, direct evidence for the contribution of beige adipocytes to whole-body metabolism remains elusive. This knowledge gap persists due to the lack of tools for selectively targeting beige adipocytes in vivo. Our preliminary data, using a novel scWAT-specific UCP1 knockout mouse model, challenge the prevailing dogma by demonstrating that UCP1 in scWAT is not required for beiging-induced tissue-specific or whole-body energy expenditure. This unexpected finding raises critical questions about the mechanisms underlying the metabolic benefits of browning. We propose to elucidate these mechanisms using innovative genetic tools and two specific aims. In Aim 1, we will determine the role of scWAT beiging in metabolic health. In Aim 2, we will investigate the impact of the creatine cycle in beige adipocytes on whole-body metabolism. This research will provide insights into the hierarchical importance of various beiging-induced adaptations and their contributions to metabolic health, advance our understanding of adipose tissue biology, and provide new insights into the development of and the metabolic pathways controlling energy consumption in beige adipocytes. Ultimately, this basic science work aims to identify new targets and strategies for the treatment and prevention of obesity in the future.

NIH Research Projects · FY 2026 · 2026-06

PROJECT ABSTRACT B-cell acute lymphoblastic leukemia (B-ALL) remain poor prognosis diseases, especially in adults, due to frequent relapse and the emergence of therapy resistance despite advances in tyrosine kinase inhibitors and immunotherapies. Although treatment options have improved, relapse continues to limit long-term survival, re­flecting a critical gap in our mechanistic understanding of resistance. This gap has hindered the development of effective, non-toxic targeted therapies. The goal of this project is to validate the RAC activator VAV3 as a negative regulator of estrogen receptor a (ERa) in B-ALL and to evaluate a novel therapeutic strategy combining a VAV3 inhibitor with the selective es­trogen receptor degrader fulvestrant in preclinical models of relapsed/refractory B-ALL including anti-CD19 ther­apy-resistant models. Our preliminary data demonstrate that pharmacological inhibition of VAV3 using IODVA 1, a small molecule we developed, enhances ERa activity and induces ERa dependency in B-ALL cells. Sequential treatment with IODVA 1 followed by fulvestrant significantly prolongs survival in preclinical models of treatment­resistant B-ALL, with durable responses after treatment cessation. We hypothesize that coordinated targeting of VAV3 and ERa represents a viable therapeutic strategy in high-risk B-ALL. In Aim 1, we will use genetic, biochemical, and pharmacological approaches to define how VAV3/ERa co-dependency regulates B-ALL proliferation and to identify growth factors besides estradiol/E2 se­creted by leukemic cells following VAV3 inhibition. In Aim 2, we will test the therapeutic efficacy of sequential VAV3 and ERa inhibition in xenograft models of relapsed/refractory and anti-CD19-resistant B-ALL, and identify mechanisms of treatment escape. Xenograft studies in immunodeficient mice are essential for evaluating effec­tive drug dosing, systemic toxicity, tumor microenvironment interactions, CNS invasion, and clonal evolution in vivo and superior in these regards to alternative in vitro or ex vivo approaches. In Aim 3, we will define the functional role of VAV3/ERa co-regulated regions, characterize clonal evolution following VAV3 inhibition using barcoding and orthogonal single-cell sequencing, and determine how ERa remodels the epigenome to sustain proliferation after VAV3 inhibition. Our long-term objective is to establish IODVA 1 plus fulvestrant as a novel, broadly effective therapeutic strategy for high-risk B-ALL. This approach has the potential to overcome resistance independent of genetic background or driver oncogene. Given the established roles RAC and VAV3 in solid tumors, these studies may also inform new targeted therapies for metastatic lung, colorectal, and breast cancers.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY This proposal describes a five-year research and career development plan that will prepare Dr. Sump to accomplish her long-term goal of becoming an independent investigator focused on leveraging digital health interventions to improve the health of all children. This proposal is specifically focused on improving the preventive care for infants with and at risk for poor weight gain in the first six months of life—a high priority population for the NICHD. Thousands of infants are hospitalized for poor weight gain every year; yet, as many as 75% have a psychosocial or environmental etiology for their poor weight gain rather than an underlying medical condition. It is imperative that we provide better support and innovative solutions in the outpatient setting in order to prevent hospitalization, which is stressful, expensive, and often avoidable. Using caregiver- engaged research and user-centered design, Dr. Sump’s work leverages previous work on an existing mHealth intervention for infants after they are hospitalized for poor weight gain. This project aims to adapt that intervention into a more comprehensive and acceptable intervention that can be deployed upstream and in the outpatient setting. In Aim 1, Dr. Sump will pursue large group, participatory qualitative methods to understand factors that promote or impede caregiver engagement with mHealth. In Aim 2, she will utilize user-centered design to adapt an existing mHealth intervention to be preventive of hospitalization and relevant to the end- users, incorporating findings from Aim 1. This will include a refinement phase in which iterative n-of-1 testing leads to an intervention that is highly usable. In Aim 3, Dr. Sump will conduct a single arm feasibility study to test the acceptability and feasibility of the adapted mHealth intervention in infants with and at risk for poor weight gain at a pediatric primary care center. To complete this research and to support her transition to an independent investigator, Dr. Sump has several competencies that she will pursue alongside the research: 1) caregiver- and community-engaged research, 2) user-centered design, 3) intervention evaluation and patient centered outcome research, and 4) academic writing and professional development. Dr. Sump has put together an accomplished and multidisciplinary mentorship team with expertise in participatory research, population health, user-centered design, and intervention evaluation with clinical trials. To prepare for a future clinical trial evaluation, Dr. Sump will have key experiential learning under her mentorship team to gain skills in trial design, ethical considerations of clinical trials, and statistical analysis. By accomplishing the aims in this proposal, Dr. Sump will leverage digital health interventions to address key gaps in the management of infants with or at risk for poor weight gain prior to hospitalization. The preliminary data from this research proposal and the skills achieved throughout the career development plan will directly support future R01 applications to expand this work to determine effective interventions for infants with poor weight gain.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Suboptimal postnatal growth is common in premature infants: as many as 50% of very low birth weight (VLBW, birth weight <1500 grams) infants weigh less than the 10th percentile at the time of discharge home. The current standard for their nutritional care is to supplement maternal breast milk with pasteurized donor breast milk; compared to formula, donor milk is associated with lower rates of necrotizing enterocolitis, a devastating disease with significant risk for morbidity and mortality. However, a more pronounced growth deficit is observed in VLBW infants who receive donor milk, even with fortification, and few strategies exist to overcome this growth disparity between donor and maternal milk. Donor milk is distinct from preterm maternal milk, with reduced protein, energy, and bioactive factors that may influence growth, including hormones such as insulin, leptin, and adiponectin. There is a critical need to improve the standard of care in the human milk feeding approach for VLBW infants, especially with donor milk, in order to positively impact growth and long-term outcomes in this vulnerable population. We will address this need by investigating the role of non-nutritive bioactive components in human milk in influencing the growth differential between donor milk and preterm maternal milk, the two primary feeding choices for VLBW infants. Specifically, the aims of this proposal are: 1. Compare insulin, leptin, and adiponectin levels in pasteurized donor milk and preterm maternal milk and characterize preterm maternal milk hormone levels over time, 2. Evaluate the association between enteral insulin, leptin, and adiponectin intake via human milk and growth in very low birth weight infants, and 3. Examine the association between select maternal risk factors and levels of insulin, leptin, and adiponectin in preterm human milk. This translational prospective study leverages an existing cohort of VLBW infants with detailed enteral intake data and growth outcomes. We will perform additional hormone quantification using enzyme-linked immunosorbent assays, crossmatch with enteral intake to determine the actual hormone exposure via human milk, then evaluate their relationships with anthropometric and body composition measurements and z-scores. This study will determine whether reduced metabolic hormone content in donor milk contributes to the growth disparity compared to maternal milk in preterm infants. This will advance the field by identifying new targets in human milk to optimize nutritional support for preterm infant growth when maternal milk is unavailable.

NIH Research Projects · FY 2026 · 2026-06

Abstract Cleft palate affects more than 1 in 1,000 children and causes significant problems in feeding, speech, increased mortality, and major challenges in social integration. In developed countries, most cleft palate patients receive surgical repair to restore an anatomically intact palate. Unfortunately, 20 – 40% of children with a repaired palate experience functional deficit known as velopharyngeal insufficiency (VPI). Many of these patients receive secondary surgery but follow-up studies often reported no significant improvement and additional complications. As increasing number of cleft patients undergo secondary surgery, VPI management remains one of the most controversial topics and a clearly unmet medical need concerning cleft palate treatment. Several authors have suggested that commonly used surgical techniques for palatoplasty could damage palatal nerve supply, contributing to VPI after cleft palate repair. However, whether deficient palatal innervation is part of cleft palate pathology and how palatal innervation is integrated with palate development are not known. We hypothesize that palatal innervation is regulated by neuronal guidance factors whose spatiotemporal expression in the developing palatal mesenchyme is regulated by resident tissue-specific transcription factors and that key guidance factors also play crucial roles in non-neuronal tissue mediated palatal morphogenesis. Interestingly, genome-wise association studies of cleft lip and palate in distinct ethnic populations have consistently detected highly significant association with variants in the netrin1 (NTN1) gene, which encodes a known important neuronal guidance factor. Ntn1 exhibits regional differential expression in the developing palatal mesenchyme and Ntn1 mutant mice exhibit cleft palate at birth. While how Ntn1 regulates palate morphogenesis is not known, we recently found that mice lacking Osr2, a key transcriptional regulator of palatal shelf growth and elevation, exhibits cleft palate associated with ectopic expression of members of the Sema3 family of repulsive axon guidance factors in the developing palatal mesenchyme and severe disruption of palatal innervation. Osr2 expression and function in the developing palatal mesenchyme integrate several key molecular pathways, including Shh-Smo signaling and the Pax9 pathways, in regulating palatal morphogenesis. We propose two specific aims to directly test our hypothesis and uncover the function and regulation of Ntn1 and Sema3 family guidance factors in palatal morphogenesis and innervation. Data from these studies will fill a longstanding critical knowledge gap regarding palate development and innervation, and provide better comprehension of cleft palate pathology that is directly applicable for improving clinical management of cleft palate treatment and patient care.

NIH Research Projects · FY 2026 · 2026-06

Project Summary. The Notch pathway is a highly conserved cell signaling pathway that plays essential roles in embryonic development and adult tissue homeostasis. Mutations in the Notch pathway underlie Adams-Oliver Syndrome (AOS), a rare disease defined by scalp aplasia cutis congenita (missing skin and skull tissue) and limb, heart, vascular, and neurological defects. Many AOS patients inherit dominant mutations within the NOTCH1 receptor, the DLL4 ligand, or the RBPJ transcription factor, all of which reside within the Notch signaling pathway. In contrast, mutations in the NOTCH2 receptor and JAG1 ligand are associated with Alagille Syndrome, a disease characterized by liver, eye, kidney, heart, skeleton, and vasculature defects. The differential expression of NOTCH1/DLL4 and NOTCH2/JAG1 receptor/ligand pairs correlates well with the organ specific defects observed in AOS versus Alagille. However, it is unclear how variants in RBPJ, which is the sole transcription factor that mediates target gene activation in the Notch pathway, causes AOS but not Alagille-like phenotypes. The goal of this grant is to use novel conditional mouse models to dissect how AOS associated variants in RBPJ alter Notch signal strength and cellular decisions. Our data supports the hypothesis that AOS- RBPJ variants do not function as loss-of-function alleles, but instead are pathological due to a sequestration mechanism of the Notch signal. Consistent with human patient data, we found that mice with an Rbpj AOS allele develop AOS-like phenotypes and have increased lethality in association with Notch1 haploinsufficiency, but not Notch2 haploinsufficiency. We propose to leverage these animal models to define the molecular defects and underlying tissue-specific pathogenesis of AOS through two aims: (1) Aim1 proposes to use a conditional AOS ‘initiating’ mouse model to study the consequences of AOS alleles on animal growth, homeostasis, wound healing, vascular development, and vascular integrity. (2) Aim2 proposes to determine how Rbpj variants cause AOS but not Alagille phenotypes by testing the non-mutually exclusive hypotheses that differences in Notch1 versus Notch2 signal composition, and/or cellular differences in co-repressor levels underlies the preferential sensitivity of N1-dependent cell types to Rbpj AOS alleles. Since Notch signaling is highly conserved to specify cell fates within virtually all organs and tissues, these studies will reveal insight into AOS pathogenesis and have a broader impact on our understanding of how the widely used Notch pathway can impact the development of specific tissues.

NIH Research Projects · FY 2026 · 2026-06

Project Summary The goal of this project is to develop a strategy to effectively eradicate leukemia-initiating cells. Leukemia- initiating cells are responsible for tumor initiation and recurrence in acute myeloid leukemia (AML), making it critically important to understand and target the biology required for leukemia-initiating cell survival. LICs are characterized by their self-renewal capacity, block in differentiation, and quiescent nature making them therapy resistant. A well characterized vulnerability of leukemia-initiating cells is oxidative phosphorylation (OxPhos) a pathway responsible for energy production. Direct OxPhos inhibition has been toxic in cancer patients. Thus, the development of approaches to target processes that regulate OxPhos in leukemia-initiating cells that are dispensable in normal cells is required. Our preliminary data shows that OxPhos is regulated by a post- translational modification called protein glutathionylation in AML cells and leukemia-initiating cells but not in normal hematopoietic stem and progenitor cells (HSPCs). These data indicate that protein glutathionylation regulation may represent a mechanism for decreasing OxPhos that could be LIC/AML specific and therefore targeting protein glutathionylation may be an approach to kill LICs with a more favorable therapeutic window than other approaches. Importantly, our data suggests that depletion of mitochondrial proteins that regulate protein glutathionylation results in reduced LIC function, induction of myeloid cell differentiation and sensitizes primary human AML cells to commonly used AML therapies but does not impact HSPCs. These data further support the potential for a therapeutic window may exist to target protein glutathionylation in AML. Based on these findings, we hypothesize that the regulation of mitochondrial protein glutathionylation is essential for LIC function by regulating OxPhos. We will examine this hypothesis by determining the molecular and biological role of protein glutathionylation in regulating leukemia-initiating cells and HSPC function using primary AML specimens, patient derived xenograft (PDX) models, and normal bone marrow specimens from healthy donors. Specifically, we will quantify leukemia-initiating cell phenotypes and function upon genetic depletion of proteins that regulate glutathionylation. Further, we will interrogate the mechanism(s) by which protein glutathionylation regulates mitochondrial energy production in leukemia-initiating cells. Taken together, our studies will be the first to establish protein glutathionylation as a novel regulator of 1) leukemia-initiating cells function and 2) OxPhos in cancer.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Up to one in six young adults in the U.S. currently use electronic cigarettes (ECs). Although these high EC use rates are fueled, in part, by adults who use ECs as tobacco cessation aids, the clinical effects of exposure on children who live with adult EC users remain unknown. What is known relates to adult EC use. Adult EC users have lower levels of biomarkers of exposure and harm compared to combustible cigarette (CC) smokers, but EC users may experience respiratory-related symptoms similar to symptoms in CC smokers. Further, EC and CC use is associated with epigenetic changes which may result in DNA methylation (DNAm) and epigenetic age acceleration (EAA), or faster DNAm-based age compared to chronological age. DNAm and EAA are biomarkers associated with an increased risk of morbidity including cancer in CC smokers and possibly EC users. Although Surgeon General’s reports warn that there is no safe level of exposure to CCs or ECs in children, some believe that EC exposure is safer than CC exposure. It is crucial to determine if this is true given the popularity of ECs. Our pilot research indicates that children with EC exposure have high tobacco exposure and oxidative stress biomarker levels, albeit at lower, but not negligible levels, compared to children exposed to CCs. No longitudinal studies have examined EC exposure patterns, biomarker levels, and respiratory health effects among children of exclusive EC users compared to children of exclusive CC smokers. To bridge this research gap, we will enroll a prospective cohort of 1-10-year-olds (N=300) who will comprise three equal groups at baseline (Month 0, M0): (1) EC Exposure Group - live with exclusive EC users, (2) CC Exposure Group - live with exclusive CC smokers, and (3) No-Tobacco Product Exposure Group - live with no tobacco product users. The objective of this project is to examine the characteristics, biomarker levels, and respiratory outcomes in children exposed to ECs vs. CCs. Biomarkers of EC and CC exposure, volatile organic compounds, propylene glycol, oxidative stress, and metals will be examined cross-sectionally at M0, at 6-months, and at 12-months (M12) in Aim 1, and then longitudinally in Aim 2. We will also examine respiratory symptoms and healthcare visits associated with EC Exposure, CC Exposure, or No Exposure over 12 months in Aim 2. In an Exploratory Aim, we will examine longer-term risk by comparing EAA and the pace of aging among exposure groups from M0 to M12. The central hypothesis is that compared to the No Exposure Group, The CC Group will have the highest biomarker levels, frequency of respiratory symptoms and healthcare utilization, and the fastest EAA, followed by the EC Exposure Group. This longitudinal project will bridge a gap that has failed to examine the pediatric effects of EC vs. CC exposure. We will study adult tobacco product use over 12 months with three waves of biomarkers and monthly respiratory outcomes, and we will explore children’s longer-term risk of cancer and age-related diseases via EAA. Results will inform recommendations for adults’ use of ECs around young children and the associated pediatric health effects.

NIH Research Projects · FY 2026 · 2026-05

Summary Obesity, now at pandemic levels, significantly increases the risk of numerous comorbidities, including sepsis- a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. A major contributor to the obesity epidemic is the widespread consumption of ultra-processed foods (UPFs), which promote excessive nutrient intake and are linked to chronic metabolic and inflammatory disturbances. These conditions activate nutrient-sensing pathways that connect nutrient excess with systemic inflammation, contributing to obesity-associated immune dysregulation. We hypothesize that obesity-associated metabolic stress enhances the production of pro-inflammatory small extracellular vesicles (sEVs), which in turn drive systemic inflammation and contribute to organ injury during sepsis. Small EVs are released by various cell types into the extracellular space and circulate in body fluids, where they are taken up by local or distant recipient cells. Our data from obese pediatric patients and healthy controls suggest that obesity imparts inflammatory traits to circulating sEVs. These vesicles, when internalized by immune cells such as macrophages, modulate inflammatory gene expression. Preliminary findings further indicate that the RNA cargo within sEVs plays a central role in regulating these immune responses. In this study, we will: 1. Define the upstream regulatory pathways that confer pro-inflammatory properties to liver-derived sEVs and evaluate their impact on sepsis outcomes in pre-clinical models. 2. Identify key molecular mediators in macrophages that drive sEV-induced inflammatory responses. Although sEV biology is rapidly evolving, the clinical implications of these vesicles remain largely unexplored. Leveraging our unique mouse models, human sEV samples, and human induced pluripotent stem cell (iPSC)- derived hepatocytes and macrophages, we aim to uncover how liver-derived sEVs shape systemic immune responses and drive organ dysfunction in sepsis. This work will clarify how obesity amplifies inflammation during critical illness and may identify novel biomarkers and therapeutic targets.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Chronic ductopenic rejection (CDR) is the most common immunologic indication for liver allograft loss in children. In CDR, the cholangiocytes that line the intrahepatic bile ducts become senescent and vanish without a restorative ductular reaction. While progressive fibrosis ultimately leads to retransplantation in CDR, the mechanistic contribution of portal fibroblasts (PF) to this process remains unexplored. Although alloreactive CD8+ T cells initiate acute cellular rejection (ACR), CDR does not respond to T-cell directed immunosuppression, suggesting a distinct underlying biology. A mechanistic understanding of underlying CDR biology is critical to identify new therapeutic approaches to mitigate CDR and prevent retransplantation. Although Th2 immunity is thought to drive cholangiocyte senescence and fibrosis in CDR, the lack of a faithful mouse model hampers mechanistic inquiry. As such, we acquired and sequenced human normal and CDR liver tissue to construct a multiome single nuclear RNA/single nuclear ATACseq dataset. This unique dataset revealed novel PF populations, including an expanded PF population marked by high expression of CXCL9. Mechanistically, CXCL9 can induce a senescence associated secretory phenotype (SASP) in cholangiocytes in primary sclerosing cholangitis (PSC), however, its function in CDR is unknown. Interestingly, we also observed a striking decrease in a separate IL33+ PF population, which we confirmed with RNAscope hybridization. In unrelated cholestatic disease models, IL-33 promotes cholangiocyte proliferation and restoration. Our novel data suggest that dyregulated PF populations contribute to CDR pathogenesis, such that potentially pathogenic CXLC9+ PFs expand and induce cholangiocyte senescence and fibrosis, while potentially facultative IL-33 PFs are lost. To begin to test the role of PF populations in cholangiocyte senescence and repair, we developed a reductive model using primary human intrahepatic cholangiocyte organoids (iCO). While normal and non-ductopenic rejecting liver readily generated iCO, the majority of CDR samples did not. This novel tractable model allows direct testing of the ability of individual cell types and their mediators to either facilitate or hamper iCO proliferation, differentiation, or senescence. Utilizing combined approaches of novel iCO-fibroblast co-culture systems and single cell spatially-resolved transcriptomics on longitudinal patient samples from patients confirmed to have CDR, we will test the following inter-related hypotheses: CXCL9+ PF from CDR drive senescence in cholangiocytes during CDR and accumulate with disease progression (Aim 1) and IL-33+ PF promote cholangiocyte proliferation and are progressively lost during CDR (Aim 2). The complementary spatial-temporal and functional data generated here will identify gene regulatory networks driving cellular interactions in CDR and reveal potential druggable targets involving cholangiocyte senescence and repair pathways, fulfilling the ultimate goal of restoring cholangiocyte health during rejection and avoiding retransplantation.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Since 1990, the biennial International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia has been the premier global meeting which spans fundamental stem cell biology and function, myeloid cell differentiation, marrow failure syndromes and myeloid cell malignancies. At the 2026 installment of the meeting (“MYELOID2026”), scientists with expertise in normal and abnormal hematopoiesis and clinicians who treat patients with myeloid leukemias, malignancies, and pre-leukemic disorders and also have active research programs in these diseases will achieve a better understanding of critical steps/factors that regulate hematopoiesis, their impact on transformation and disease resistance, and their potential relevance in clinical settings. MYELOID2026 will stimulate the community with collaborations on active projects, educate trainees, and “cross pollinate” critical and influential sectors of multiple myeloid biology fields. Moreover, the meeting size, meeting program, and ratio of trainees to faculty at the MYELOID meetings, provide trainee attendees ample opportunities for networking and faculty engagement for project discussions. We expect several landmark studies for the respective fields of normal hematopoiesis, stem cell biology, and myeloid malignancies to result from presentations by attendees. MYELOID2026 will bring together world renowned scientists, clinicians, and trainees to improve our understanding of hematopoietic development and differentiation, stem cells, and the evolution of myeloid malignancies.

NIH Research Projects · FY 2026 · 2026-05

Project Summary The nuclear envelope can rupture in various age-associated conditions, including cellular senescence, neurodegenerative disorders, cancer, myocardial infarction, and premature aging. Nuclear rupture can lead to pathological consequences, such as gene expression defects, DNA damage, and innate immune activation, or instead be resolved through endogenous repair. How these divergent outcomes are regulated remains unknown. This is a critical gap in our understanding, because uncovering the underlying mechanisms could enable strategies to prevent rupture or promote repair. We hypothesize that proteins recruited to nuclear rupture sites – most of which remain unidentified – regulate these cellular responses. To test this hypothesis, we will systematically identify proteins recruited to nuclear rupture sites. Our disease model is LMNA-related dilated cardiomyopathy (LMNA-DCM), a fatal heart disease. LMNA encodes Lamin A/C, a nuclear lamina protein that maintains nuclear envelope integrity. We have developed cardiomyocyte-specific Lmna-knockout mice (LmnaCKO) as a model of LMNA-DCM and observed frequent nuclear rupture in the heart, as in the patient hearts. In Aim 1, we will identify proteins recruited to nuclear rupture sites in LmnaCKO cardiomyocytes using in-vivo BioID. As baits, we will use three rupture-associated proteins that we found to accumulate at rupture sites in LmnaCKO hearts: namely, BANF1, which binds DNA at rupture sites; LEMD2, a transmembrane protein implicated in membrane repair; and catalytically inactive cGAS (icGAS), which marks both ruptured and repaired nuclei. In Aim 2A, we will validate the localization of candidate proteins identified in Aim 1 and determine whether they preferentially associate with ruptured or repaired nuclei. In Aim 2B, we will assess the functional roles of select candidates by depleting them in vivo and measuring their effects on nuclear rupture and repair frequencies. If successful, this project will yield the first systematic identification of nuclear rupture-associated proteins in any cellular context. By defining the “rupture proteome”, this project has the potential to uncover novel regulators of nuclear rupture and repair, offering the potential therapeutic targets for LMNA-DCM and other age-related conditions characterized by nuclear envelope rupture.

NIH Research Projects · FY 2026 · 2026-05

PROJECT ABSTRACT Congenital heart disease (CHD) occurs in approximately 40,000 infants in the United States each year. The National Heart, Lung, and Blood Institute (NLHBI) launched its Bench to Bassinet Program (B2B) in 2009 to overcome the major barriers in translational research, identify the causes of human CHD, and improve outcomes for individuals with CHD. Through the Congenital Heart Disease GEnetic NEtwork Study (CHD GENES), the B2B program has enrolled over 14,000 participants with CHD and 18,000 family members, conducting genomic sequencing to identify an estimated 25% of previously unexplained CHD cases. Despite these advances, critical gaps persist in our understanding of how genetic variants influence genotype- phenotype correlations and long-term outcomes in CHD. Although not initially designed as a longitudinal cohort, the NHLBI recognized the unique potential of the CHD GENES and directed the coordinating center (CC) to organize deep phenotyping and re-enrollment of a subset of participants for an in-person clinical assessment and to make the data available to the scientific community as the B2B Congenital Heart disease Advancing New understanding in GEnomics (CHANGE) Cohort. The new iteration of the CC is a unique, integrated combination of world-leading cardiovascular and clinical/translational research expertise, advanced infrastructure, outstanding operational support, and state-of-the-art technology. The specific aims are to: 1) Establish and maintain the B2B CHANGE Cohort, 2) Create a unique resource for CHD research by integrating new data sources with the existing clinical and genomic information maintained in the B2B DataHub (HeartsMart) and shared with NHLBI’s BioData Catalyst system, and 3) Ensure the CHD community has the necessary access, tools, and support to translate B2B data into improved health and quality of life for those affected by CHD. B2B CHANGE will be established using a multifaceted and patient-informed cohort outreach and engagement approach incorporating nationally recognized expert leadership and consultation and adaptation to local contexts as appropriate. Innovative clinical assessments and technical advancements to HeartsMart will expand and enrich existing phenotyping approaches, extend the duration of follow-up, and allow for new biological sample acquisition for future mechanistic and translational studies. Through resources including HeartsMart and BioData Catalyst, and extensive outreach, education, and engagement, the CC will ensure the CHD community has access to this vital resource to support rigorous, independently funded, investigator-initiated ancillary studies. The B2B CC has provided excellence in administrative support and coordination for the B2B program for the previous two funding cycles and will continue to be a successful partner with site investigators, the NHLBI, and the CHD community, leading the coordination of knowledge and data for this important cardiovascular research effort.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Cognitive disengagement syndrome (CDS; previously termed sluggish cognitive tempo) is a set of behavioral symptoms characterized by excessive daydreaming, slowed thinking, and mental confusion. Despite being overlooked in psychopathology research for decades, it is now established that CDS symptoms (1) are distinct from other psychopathology including ADHD and internalizing symptoms, (2) can be reliably measured, and (3) increase across development. CDS is also associated with several significant areas of functional impairment including internalizing symptoms, suicide risk, and interpersonal difficulties. As CDS research advances, there is a need for developmentally-informed research that can advance theoretical models of CDS within broader models of psychopathology. We propose that CDS may be an important yet understudied transdiagnostic vulnerability to psychopathology that can inform models of heterotypic comorbidity while also being an untested gateway to the development and rise of internalizing problems across adolescence. However, there is a dearth of research examining CDS during adolescence, particularly with a longitudinal design. To address this gap in the existing scientific evidence base, we recently recruited a large, diverse community sample (N=341; ages 10-12 years) enriched for CDS symptoms to ensure the full range of CDS was represented. Participants are assessed at three timepoints over a 2-year period (i.e., baseline, 1-year follow-up, 2-year follow-up). Retention rates currently exceed 93%. Given its size and scope, this study comprises the most rigorous CDS study to date. However, despite the ongoing study being the only CDS-specific longitudinal sample in adolescence, it is limited to 3 timepoints over a 2-year period when the maximum age of participants will be 14 years. We thus have a unique opportunity to leverage this large, highly unique sample by conducting 4 additional assessments which will result in a total of 7 annual visits in a sample spanning the ages of 10-18 years. In this study we will (1) examine CDS as a transdiagnostic predictor of psychopathology (i.e., internalizing symptoms, dissociation, borderline features, insomnia) and suicidal ideation across adolescence, (2) test interpersonal functioning as a mechanism of the prospective link between CDS and internalizing psychopathology, (3) explore individual and diversity dimension factors that may moderate the prospective relation between CDS and internalizing, including trauma exposure, biological sex, and socioeconomic status, and (4) establish CDS in relation to theoretically-linked behavioral units of analyses, including task-assessed mind-wandering, processing speed, and negative attribution bias. Findings from our proposed 7-wave longitudinal design supporting the hypothesis that CDS uniquely predicts increased internalizing problems across the second decade of life would make a major advance in developing theoretical models of CDS, positioning CDS within broader hierarchical taxonomies of psychopathology, and providing avenues for targeted clinical assessment and treatment.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT/SUMMARY Integrative multiomics prediction of fetal origins and perturbations for chILD Childhood interstitial lung diseases (chILD) encompass a wide range of rare but often severe respiratory disorders that diffusely affect lung parenchyma, particularly in neonates and infants. These conditions significantly contribute to infant mortality and morbidity and can influence respiratory health outcomes well into adulthood. Disruptions in fetal lung development play a crucial role in the etiology and pathogenesis of chILD; however, the precise fetal lung cell origins and molecular mechanisms underlying individual chILD remain poorly understood, even in cases linked to known genetic variants. This underscores the need for mechanistic and omics study of chILD. We have employed high- resolution spatial and single-cell multiomics techniques to analyze chILD caused by variants in FOXF1 or TBX4, two important genes in fetal lung development, and identified cellular and molecular alterations in individual chILD. However, most existing chILD omics studies, including ours, relied on samples collected postnatally or in later disease stages, limiting our insight into early disruptions in fetal lung development. Recently, multiple large-scale single cell multiomics and spatial transcriptomics datasets of human fetal lung were published, offering an unprecedented opportunity to bridge this gap. Here, by leveraging these existing fetal lung and chILD datasets, we will perform a secondary analysis and develop FLUME, a human fetal lung multiomics cell atlas with computation models to predict fetal origins and perturbations for individual chILD. We hypothesize that the application of FLUME can identify fetal lung cell states and genes that, when perturbed, cause cellular and molecular phenotypes consistent with alterations in chILD. This hypothesis will be tested via two specific aims. In Aim 1, we will integrate existing single cell multiomics datasets of fetal lung to construct a comprehensive cell atlas of human lung development, covering all five stages from embryonic to alveolarization. We will focus on defining cell states, transitions, and the underlying gene regulatory networks (GRNs) using both single cell RNA-seq and ATAC-seq patterns and refined by spatial patterns. In Aim 2, we will train machine learning models on the integrated data from Aim 1 to predict candidate fetal cell states for cell populations altered in chILD. We will perform in silico perturbation analysis to identify the cell states and genes that cause cellular and molecular changes consistent with disease alterations. Results from this study will advance our understanding of key pathways and gene networks in normal and aberrant lung development, inform further mechanistic studies of chILD, and potentially guide the development of early diagnostic markers and targeted interventions for chILD. The integrated and curated data will also facilitate fine-tuning of large AI pretrained models for lung development and diseases.

NIH Research Projects · FY 2026 · 2026-04

Summary Tuberous Sclerosis (TS) is a rare genetic disorder associated with benign tumors and neurological symptoms including autism and epilepsy. TS is caused by mutations in the genes coding for tuberous sclerosis complex proteins 1 and 2 (TSC1/2). Mutations in TSC2 are both more common and produce more severe disease phenotypes. TSC1/2 regulate signal transduction through mTOR, a major signaling hub important for cell growth, cell survival, neuroinflammation and other cellular functions. Neurological symptoms are major contributors to morbidity in TS, with the majority of affected children developing intractable epilepsy. FDA- approved mTOR inhibitors reduce seizures in some individuals with TS and in TS mouse models. However, not all TS patients respond clinically to mTOR inhibitors and treatment can have problematic side effects. Moreover, the severity of TS is highly variable with disease manifestations ranging from minimally symptomatic to life-threatening. Mechanisms underlying this variability are poorly understood and have been identified as one of five priority focus areas in the NIH strategic plan for TS research. Considerable effort is being made to understand the impact of secondary somatic mutations, genetic modifiers, and environmental factors but surprisingly little is known about the biological consequences of the primary mutations in TSC1/2. It has been proposed that mutations lead to complete loss of function, but this has not been rigorously tested and seems unlikely, considering that mutations are highly diverse; from single point mutants to large deletions spanning entire exons. This R21 application, therefore, has two goals. Firstly, we will test the hypothesis that distinct human TSC2 mutations contribute to the variability in disease severity. Secondly, mutations will be tested using a platform optimized for a personalized medicine approach for infants newly diagnosed with TS. The long-term goal is to be able to provide data on the functional effects of a child’s TSC2 mutation by their first birthday, guiding prognosis and treatment. The rapid screening platform utilizes a cre/lox system in Tsc2fl/fl mouse cells and intact mice, facilitating a lentivirus-based strategy to delete the mouse gene and replace it with the human mutation. Lentiviral vectors can be easily modified to express different human TSC2 variants for patient testing. Initial proof-of-concept studies will test six human mutations in cell culture and in intact mice, focusing on neuronal morphology, epilepsy severity and single nuclei RNA-Seq analyses as a first step to understand differences in mutant-induced molecular changes. Mutations affecting different protein functional domains and covering a range of clinical severities were selected. The project will benefit from synergistic collaborations between CCHMC’s TS clinic and basic science labs. This research may be a first step towards the development of rapid screening platforms useful for diagnosis and drug discovery in TS, making a personalized medicine approach for TS feasible.

NIH Research Projects · FY 2025 · 2026-04

ABSTRACT Understanding and mitigating drug-induced liver injury (DILI) in children is crucial for pediatric healthcare. Children are more prone to liver damage due to differences in drug metabolism, liver development, and unique susceptibilities. DILI can cause immediate health risks and long-term issues like liver failure or chronic liver disease. Since children often need medications for chronic diseases such as epilepsy, infections, and pain, ensuring the safety of drugs is vital. Addressing DILI in children through advanced methods not only improves drug safety but also supports personalized medicine, enhancing care quality and reducing adverse drug reactions. For example, acetaminophen, commonly used for pain and fever, can cause severe liver damage. Valproic acid, used for epilepsy, also poses a risk of liver toxicity, especially with long-term use. In this proposal, we would like to investigate mechanisms of toxicity of acetaminophen, valproic acid, amoxicillin- clavulanate, cannabidiol (CBD), and isoniazid, which covers critical pharmaceuticals in pediatric healthcare, and develop biomarkers of pediatric DILI caused by these pharmaceuticals. The proposal has two main aims. Aim 1 is to evaluate the effect of selected drugs on liver toxicity markers using a sandwich cultured human hepatocyte model leveraging primary human hepatocytes from pediatric and adult donors. This will involve measuring proteomic and metabolomic biomarkers in drug-treated hepatocyte lots from infants, children, adolescents, and adults to understand age-specific mechanisms of DILI. The study will also analyze proteomics data of extracellular vesicles and untargeted metabolomics of media to identify molecular changes and drug-protein adducts. These data will be integrated into mathematical models using quantitative systems toxicology (QST) models to predict pathways and mechanisms of DILI. Aim 2 will measure the effects of acute and prolonged drug exposure using liver microphysiological system (MPS) using standardized liver tissue chip. By analyzing proteins and metabolites released in the media from these systems, the study will assess immediate and long-term impacts on liver function and toxicity in both pediatric and adult livers. Overall, utilizing advanced methodologies such as proteomics, metabolomics, and complex in vitro models, including MPS, the research will assess DILI across various pediatric age groups. Integrating these findings into mathematical models will provide a deeper understanding of DILI mechanisms and potentially identify specific biomarkers relevant to children. Ultimately, when validated in clinic, pediatric DILI candidate biomarkers will enhance drug safety profiles, inform better prescribing practices, and support personalized treatment approaches in children.

NIH Research Projects · FY 2026 · 2026-04

Project summary Idiopathic pulmonary fibrosis (IPF) is the single most common and lethal type of lung fibrosis of unknown cause, which starts with the build-up of scar tissue from the edges of the lung, and advances toward the inside center over time. This intriguing edge-to-center fibrotic progression suggest the presence of unique biological or physical cues in the lung periphery that initiate the disease, the study of which is still in its infancy. Given the fact that few treatment options are available once interstitial fibrosis develops, early diagnosis and treatment are thus critically important, which is hindered by our poor knowledge on the etiology of fibrotic progression. By using cutting-edge technologies including lineage tracing, mouse modeling and multimodal single cell sequencing, Dr. Xu found that elevated mechanical tension drives the differentiation of a novel population of fibroblasts in the lung periphery, leading to the subpleural fibrosis. These fibroblasts are characterized by expression of Wilms' tumor 1 (WT1), signatures of Epithelial-Mesenchymal Transition (EMT), and secretion of multiple kinds of chemokines and cytokines. Fibrosis progression is achieved through additional lung injury, suggesting that a synergistic effort between these WT1+ subpleural fibroblasts and injured epithelial cells may drive the progression of pulmonary fibrosis. These preliminary data raised the Central Hypothesis that WT1+ subpleural fibroblasts function as a stromal niche that drives the progression of pulmonary fibrosis, which will be rigorously tested here in three Specific Aims: Aim 1. To determine the cellular origins and molecular drivers of WT1+ SPFBs [K99] To address the progenitors of WT1+ SPFBs, and transcription factors that drive their induction. Aim 2. To determine if WT1+ SPFBs act as a stromal niche to promote fibrosis progression [K99/R00] To address the biological roles of WT1+ SPFBs in promoting fibrosis progression. Aim 3. To determine if the recruitment and function of myeloid cells in the subpleural region promote pulmonary fibrosis progression [R00] To address the contribution of subpleural myeloid cells, which are hypothesized to be recruited by WT1+ SPFBs, to fibrosis progression. Dr. Xu is well on track towards his career goal as an independent investigator, evidenced by his multidiscipline training record and academic productivity. To accomplish this, he will receive support from his outstanding and complementary mentor committee, including Dr. Xin Sun (primary mentor), Dr. Zea Borok (co- mentor, lung fibrosis), Dr. Laura Alexander (co-mentor, immunology) and Dr. Kyle Gaulton (co-mentor, epigenomics/single cell technology).

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Food insecurity is a demonstrated risk factor for disordered eating (e.g., loss of control eating) and cardiometabolic health concerns, and Hispanic/Latino adolescents experience disproportionate risk. The proposed project aims to understand the mechanisms underlying the relationships amongst food insecurity, loss of control eating, and cardiometabolic health using longitudinal data capture over a 6-month study period (i.e., data collection at Baseline, 3-months, 6-months) in Hispanic/Latino adolescents. This will occur in conjunction with qualitative interviews with their caregivers (inclusive of Spanish-speaking caregivers) regarding intergenerational factors affecting eating behavior, experiences of community food access, and perceived needs pertaining to food insecurity and healthful eating. Fasting labs to assess each adolescent’s cardiometabolic health indicators will occur at Baseline and 6-month follow-up visits. These data will inform intervention development with planned steps to define modifiable targets of the intervention, adapt evidence-based intervention components tailored to participant needs, and refine intervention content based on focus group feedback (ORBIT Phase Ia and Ib). The career development plan will provide the K23 PI, Dr. Bejarano, with necessary training in community-engaged research strategies with Hispanic/Latino populations, ORBIT intervention development and clinical trials, and prevention science with mentorship from interdisciplinary experts in these areas (Drs. Zeller, Shah, Shomaker, and Jacquez). Upon completion of the K23 career development and research plan with the support of her mentorship team, Dr. Bejarano will be prepared to test an adapted intervention designed to be preventive to disordered eating and cardiometabolic health risk. This study is novel in its assessment of individual experience and qualitative perspectives of food insecurity and loss of control eating in Hispanic/Latino adolescents, in relation to longitudinal cardiometabolic health outcomes, with the inclusion of perspectives of Spanish-speaking caregivers. Dr. Bejarano’s K23 aligns with priorities stated by the National Institute of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) to investigate multi- level impacts of food insecurity, develop novel interventions, and sustain a scientific workforce prepared to contribute to the institutes’ missions to promote cardiometabolic health and prevent disease.

NIH Research Projects · FY 2026 · 2026-04

Myelodysplastic Syndromes (MDS) are a group of bone marrow failure disorders caused by clonal expansion of hematopoietic stem cells (HSC) that fail to produce mature blood cells of sufficient quality and quantity. The disease-causing HSC bear acquired mutations that confer a selective advantage compared to other HSC but are detrimental to hematopoiesis. Typically, the mutations confer increased proliferation and survival upon HSC and their progeny, creating a hypercellular bone marrow with increased proportions of immature myeloid cells. In contrast, mutations in DDX41, an essential RNA helicase, cause reduced proliferation and survival of hematopoietic progenitors and yet contribute to about 4% of MDS cases. DDX41-mutated MDS most often occurs in individuals with inherited heterozygous mutations in the gene, 50-70% of which are truncating (frameshift or loss of translation start) and are thus considered loss-of-function. The other 30-50% of these are missense mutations, whose effect on protein function is largely unknown. The most common acquired mutation occurring in these patients is a second-hit mutation affecting the other allele of DDX41, typically causing the amino acid change R525H. Unique features of DDX41-mutated MDS include a hypocellular bone marrow, few co-mutations, and relatively slower disease progression. Our published and preliminary data indicate that the most common combination of DDX41 mutations observed in patients (truncating/R525H) causes a profound defect in hematopoietic progenitor cell proliferation and survival. Remarkably, our patient sequencing studies demonstrate that HSC bearing biallelic DDX41 mutations clonally expand and dominate the HSC pool, accounting for over 90% of HSCs in 11 out of 11 patients analyzed but only 5-25% of total bone marrow cells. These data and our published mouse models indicate that biallelic DDX41 mutations are favored in HSC but strongly detrimental to progenitor cells. Mechanistically, we found that DDX41 is required for ribosome biogenesis through its function in splicing at small nucleolar RNA (snoRNA) genes. Thus, biallelic DDX41 mutations confer reduced protein synthesis, which is a cause of the progenitor cell viability defect. HSC maintain a lower protein synthesis rate than progenitors, even when cycling, likely for protection from proteotoxic stress, which contributes to aging-associated decline of HSC and other tissue-specific stem cells. We hypothesize that biallelic DDX41 mutations are positively selected in aging HSC pools due to a reduction in proteotoxic stress. In the case of germline missense mutations, this requires dominant negative effects by the acquired R525H mutation to cause reduced protein synthesis and the associated stem cell expansion and progenitor cell defect. To test these hypotheses, we propose to determine the effect of combined germline and acquired missense DDX41 mutations on HSC function through analysis of MDS patient samples and mouse models, and then we propose to determine if proteotoxic stress is the driver of the clonal advantage of biallelic DDX41-mutated HSC in aging bone marrow through analysis of genetically and temporally precise mouse models of the disease.

NIH Research Projects · FY 2026 · 2026-04

Summary Drug-induced pancreatic injury (DIPI) is a severe and underappreciated adverse drug reaction with substantial clinical and drug development challenges. Recently, DIPI has been classified as a leading cause of acute pancreatitis in children and the third most common etiology in adults. DIPI is associated with a more severe disease course compared with other pancreatitis etiologies. More than 500 drugs have been linked to pancreatitis, but the underlying causes of DIPI are still not fully understood. Effective tools for identifying high- risk medications, managing drug combinations, and defining individual patient risk profiles are currently unavailable. This critical knowledge gap hinders optimal patient management and informed drug development decisions related to pancreatic toxicity. The overarching goal of this innovative study is to leverage large-scale transcriptomic data, real-world evidence from electronic health records (EHRs), FDA systems, network propagation, and experimental approaches to systematically characterize DIPI. Our central hypothesis is that integrated analyses of multi-omics data, real-world evidence, and systems pharmacology techniques can reveal novel drug targets, therapeutic candidates, and the underlying mechanisms of DIPI. In Aim 1, we will employ computational approaches on pancreatitis transcriptomic signatures and 1.4 million perturbagen profiles to identify putative pancreatitis-modulating drugs (protective or harmful). This compendium will enable risk assessment and reveal potential repurposing opportunities. In Aim 2, we will mine the FDA's adverse event database to identify drug combinations that mitigate DIPI risk, starting with the ~120 known DIPI-causing drugs. The top combinations will be validated using longitudinal EHR data. In Aim 3, we will map DIPI modulators and pancreatitis gene sets onto molecular networks using propagation algorithms to identify overlapping pathways and therapeutic targets. This will be achieved by prioritizing the empirical validation of both established and newly identified pancreatitis modulators, with a focus on ex vivo studies using both mouse and human acinar cells to assess the effects of these selected compounds. The expected outcomes include comprehensive resource (DIPIModDb) of pancreatitis risk-modulating (causing or protecting from pancreas injury) drugs, clinically actionable mitigating drug combinations for DIPI, and mechanistic insights into novel therapeutic targets. These findings will transform clinical practice by enabling better risk assessment, informed therapeutic decisions, and the development of interventions for this devastating adverse event. From a drug development perspective, our results will guide preclinical studies on the safety of pancreatitis during drug discovery. In summary, this multi- pronged strategy leverages multiple big data resources and experimental validation studies to address critical gaps in our knowledge of DIPI. The collective expertise of our team will ensure the successful achievement of the specified objectives, resulting in a reduction in the DIPI burden, enhancement of patient care, and acceleration of the development of pancreatitis medications.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY During adolescence, individuals with attention-deficit/hyperactivity disorder (ADHD) often show escalating academic and social impairments and comorbid psychopathology, a rapid decline in medication use and adherence, less engagement in psychosocial treatments, and limited data to guide those treatments. Sleep has emerged as a promising new intervention target to mitigate this confluence of undertreatment and risk. Even compared to their notoriously sleep-deprived typically-developing (TD) peers, adolescents with ADHD have worse sleep, irrespective of whether they are taking ADHD-targeting medications. Growing evidence links this poor sleep to functional impairment, and our team has shown these links to be causal. Experimentally shortened sleep causally degrades core inattentive symptoms and common comorbid symptoms for adolescents with ADHD. Conversely, the effects of lengthening sleep in these studies rivaled those of more intensive behavioral treatments. Sleep-targeted interventions show tremendous promise for adolescents with ADHD, but other observational data from our group also highlight a crucial puzzle to unlock this promise: how to best integrate sleep duration with sleep timing. Adolescents with later chronotypes (“owls,” who prefer later bedtimes and rise times) perform worse in school than those with earlier chronotypes (“larks”), even after controlling for sleep duration and quality. We assert that this reflects a “misalignment effect”: a timing mismatch between the early demands of school and the late circadian phase (internal body clock) of owls. Emerging data from our labs suggest that attention in TD adolescents is improved by lengthening sleep only if it is timed to align with the individual’s circadian phase. If this also holds true for adolescents with ADHD, it would light new paths towards individualized interventions that address misalignment. In addition, evidence suggests that adolescents with ADHD may have delayed circadian phase, which would make morning activities (e.g., school) misaligned. If so, it would point to circadian-informed interventions for adolescents with ADHD as a group. To guide and justify circadian-informed intervention development, we propose two concurrent studies that will yield complementary data. The first is an observational school-year study that will determine, for the first time, test whether adolescents ages 13-17 with ADHD (n=85) average a later circadian phase than sex- and age- matched TD peers (n=85), and whether misalignment is linked to real-world deficits in attention and functional outcomes. The second is a summer mechanistic clinical trial that will test, also for the first time, the causal impact of circadian misalignment on attention in adolescents with ADHD (N=50). Findings will provide unique insight into the role of circadian factors in adolescent ADHD, concurrently testing cause-effect relationships and real-world implications. If, as we predict, circadian misalignment is common amongst adolescents with ADHD, causally impacts attention, and is linked to real-world functional impairment, it would open important new avenues for intervention in a difficult-to-treat population at high risk for poor outcomes.

NIH Research Projects · FY 2026 · 2026-02

PROJECT ABSTRACT Intrahepatic bile duct (IHBD) paucity is a major cause of pediatric liver disease, leading to significant morbidity and mortality. It results in chronic cholestasis, and often necessitates liver transplantation, which remains the only definitive treatment. IHBD paucity is associated with conditions such as Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and biliary atresia, yet no clinical interventions currently exist to augment IHBD architecture. Hepatocyte-to-cholangiocyte reprogramming—a process whereby hepatocytes acquire cholangiocyte characteristics—has emerged as a potential therapeutic approach. Genetic models of IHBD paucity demonstrate the ability of hepatocytes to reprogram under cholestatic stress, forming functional IHBD networks that effectively drain bile and persist after injury reversal. Importantly, reprogramming appears to require a stereotyped selective engagement of chromatin remodeling and transcriptional activation as well as repression programs, enhancing the completion of the hepatocyte conversion. Key barriers remain, such as fully repressing the original hepatocyte program to prevent hybrid cell states or deleterious outcomes, like cancer. Unique human-mouse integrated datasets, including liver samples from infancy through adulthood, provide new insights into temporal competence for reprogramming, showing that factors like age, spatial zonation, and gene regulation influence outcomes. Interestingly we have found that hepatocyte age impacts their chromatin accessibility at cholangiocyte-specific loci. The research explores two specific aims: 1) testing how Notch threshold levels and temporal factors dictate zonation-specific reprogramming sensitivity, and 2) defining Prdm16’s role, as a histone methyltransferase, in regulating chromatin and facilitating hepatocyte-to-cholangiocyte reprogramming. By combining cutting-edge techniques, including refined lineage-tracing mouse models, paired RNA expression and chromatin accessibility data, and human liver datasets, the study seeks to overcome translational barriers. This research promises to expand our understanding and the molecular underpinnings of reprogramming to optimize future cell/gene therapies with the promise to improve therapies for IHBD-related diseases like ALGS.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Millions of people in the US are impacted by gastrointestinal diseases including Inflammatory Bowel Disease (IBD), Metabolic Disfunction Associated Steatotic Liver Disease (MASLD) and Pancreatitis. There are only a small number of drugs for IBD and MASLD, and none for Pancreatitis, making this a critically significant clinical question. Animal models have proven inadequate surrogates for these diseases and reliance on current preclinical evaluations are considered to be among the most problematic steps in drug discovery. The goal of Cincinnati Advanced NAM Development and Operational Research center (CANDOR) is to develop combinatorial New Approach Methodologies (NAMs) that more accurately model the pathophysiologic complexity and drug responses in patients with these gastrointestinal (GI) diseases. We have established an interdisciplinary team of collaborators of clinicians, scientists, experimental and computational biologists with a history of developing in vitro organoid and in silico NAMs with a focus on inflammatory diseases of the GI tract. CANDOR will provide a collaborative pipeline starting with existing cohorts of deeply phenotyped patients with IBD, MASLD, and Pancreatitis. Clinical data and patient samples will be used to build in silico NAMs, based on molecular pathways and cell-cell interactions that corelate with patient outcome and drug response. Each disease will have a corresponding in vitro NAM comprising intestinal, liver, and pancreatic organoids each with immune cells. Pluripotent stem cell banks have been generated from patients with each of these diseases, and healthy controls, and all organoid platforms are established and benchmarked to human samples. The aims of CANDOR are to establish in vitro NAMs that accurately model clinical features of IBD, MASLD, and Pancreatitis; to build disease-focused in silico NAMs that are based on gene regulatory, cell-cell interactions, and pharmacometric models from patients and combine these with data from in vitro NAMs; and to validate and disseminate combinatorial NAM technologies through training, outreach, and distribution.