University Of Colorado Denver

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY Ependymoma (EPN) is fatal in 50% of children and has not seen any therapeutic improvements in over 30 years. Standard therapy remains limited to surgery, radiation, and chemotherapy in limited situations. In the past decade our understanding of the molecular biology of EPN has been advanced by molecular analysis of patient samples but these advances have failed to improve outcomes. Genomic studies clearly define multiple subgroups including Posterior fossa A and B as well as supratentorial subgroups. Despite these advances the heterogeneity in EPN remains a problem. To address this problem, we performed single cell RNA sequencing analysis of EPN patient samples and identified an undifferentiated progenitor population that expresses high levels of pluripotent cell markers. In parallel we performed an unbiased epigenome-wide RNAi screen targeting 410 chromatin regulators to identify novel epigenetic regulators critical for EPN cell growth. We identified the Polycomb repressive complex 1 (PRC1) protein BMI1 as a top hit, that when depleted or chemically inhibited severely suppressed EPN cell growth. Interestingly BMI1 is most highly expressed in the undifferentiated population identified by our scRNA-seq and associated with worse outcomes. Importantly the functional significance of BMI1 has not previously been evaluated in EPN. We hypothesize that high expression of BMI1 promotes de-differentiation and self-renewal of the UEC subpopulation, thereby locking the cells in a highly tumorigenic stem-like state. To address our hypothesis, we will first investigate the inhibition of BMI1 function on PFA tumor cell self-renewal and differentiation of aggressive PFA subpopulations in vitro. We will then establish the therapeutic efficacy of targeting BMI1 with novel small molecule inhibitors in EPN in vivo. Completion of this work will establish a direct role for BMI1 in EPN stem cell differentiation and provide justification for use of BMI1 inhibitors in human pediatric clinical trials.

NIH Research Projects · FY 2026 · 2023-04

PROJECT ABSTRACT Our goal is to establish a new framework for understanding the regulation of fetal growth. To do so, we will demonstrate novel roles for fetal glucagon and maternal placental lactogen. Current dogma holds that the mother's nutritional and hormonal status, uterine blood flow, and early events in placental development regulate placental nutrient delivery and fetal growth. However, knowledge gaps in this understanding have prevented progress towards successful treatment of disordered fetal growth during complications of pregnancy. This proposal will show how fetal glucagon inhibits uterine blood flow and placental nutrient delivery by inhibiting secretion of placental lactogen into the maternal circulation. We have recently demonstrated that experimentally increasing fetal glucagon concentrations with direct fetal glucagon infusions into late gestation fetal sheep lowers uterine blood, placental uptake of nutrients and oxygen from the maternal circulation, placental delivery of amino acids to the fetus, fetal plasma concentrations of amino acids, fetal plasma concentrations of the anabolic growth factors insulin and IGF-1, and fetal protein accretion. These were associated with a 13% reduction in fetal weight after just a nine-day infusion. Additionally, we have demonstrated that experimentally lowering placental lactogen in pregnant sheep results in lower uterine blood flow and placental nutrient delivery independent of its classically described role in regulating maternal nutrient metabolism. We have repeatedly shown that increasing fetal amino acids raises fetal glucagon concentrations. Taken together, these data support our overarching hypothesis: fetal glucagon matches placental nutrient delivery to fetal metabolic demand by inhibiting PL secretion. This hypothesis will be tested in pregnant sheep, isolated human primary trophoblasts, and uterine and myometrial arteries isolated from pregnant sheep and humans, respectively. In Aim #1 we will show that the mechanism by which fetal glucagon inhibits fetal growth is by lowering placental amino acid delivery and fetal amino acid concentrations. In Aim #2 we will demonstrate that the mechanism by which fetal glucagon inhibits uterine blood flow and placental nutrient delivery is by lowering placental lactogen secretion. In Aim #3 we will establish the mechanism by which glucagon inhibits placental lactogen secretion. This proposal will be the first mechanistic physiological investigation into fetal glucagon as an inhibitor of uterine blood flow, placental nutrient delivery, and fetal growth and placental lactogen as a vasodilator in the uterine circulation. The impact will be to shift the paradigm for our understanding of the regulation of fetal growth. This is required if we are to make new advances into the management of disordered fetal growth in pregnancies complicated by placental insufficiency, preeclampsia, diabetes, maternal obesity and other conditions.

NIH Research Projects · FY 2026 · 2023-04

Project Abstract The molecular mechanisms and the clinical predictors of life-threatening arrhythmias in patients with dilated, nonischemic cardiomyopathy (DCM) remain elusive, hampering adequate prevention and treatment of sudden cardiac death (SCD) and malignant ventricular arrhythmias (VA) in this population. Our application will address this unmet need. Our established team of investigators from the University of Colorado and Stanford University has assembled preliminary data and proof-of-concept experiments to tackle three complementary aims, which will comprehensively fill critical knowledge gaps in life-threatening VA and SCD risk in DCM. We hypothesize that two main mechanisms are involved in VA/SCD in DCM: genetic factors (“arrhythmogenic” genes) and cardiac fibrosis. We will address these hypotheses with three independent but complementary Specific Aims (clinical, translational and mechanistic) designed to translate the discovery of mechanisms and delineation of prognosis into a precision medicine approach. Specific Aim 1 will define genotype and phenotype predictors of malignant VA and SCD in DCM. Our preliminary studies show that phenotype, such as myocardial fibrosis, and gene mutations significantly increase the risk of VA/SCD. Thus, we hypothesize that a clinical multidisciplinary approach including genotype and advanced imaging can precisely identify DCM patients at risk of SCD. Using deep phenotyping, outcome measures, and NextGen sequencing in the Familial Cardiomyopathy Registry (1,316 DCM subjects), we will generate a SCD risk prediction score for clinical use. Specific Aim 2 will identify the transcriptome signature of VA. We found that explanted hearts of patients with arrhythmogenic DCM have a distinct transcriptional signature. Thus, we hypothesize that, in advanced- stage DCM, lethal arrhythmias are driven by genetically determined transcriptional signatures. We will leverage whole genome and transcriptome sequencing data from our NIH/NHLBI TOPMed project (X01 HL139403: 1078 explanted hearts, 504 DCM, 140 controls) to identify gene-specific dysregulated pathways predicting high-risk VA. Specific Aim 3 will elucidate the molecular mechanisms of arrhythmogenic genes. Our preliminary data in mutant human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) show evidence of intrinsic electrical instability. However, the role of cardiac fibroblasts and CM/CF cross-talk in arrhythmogenesis remains unknown. We hypothesize that arrhythmogenic DCM genes activate fibroblasts and induce arrhythmia, either directly or indirectly through their interaction with cardiomyocytes. hiPSC-CM and cardiac fibroblasts (hiPSC-CF) will be generated from 60 patients from our Registry (Aim 1) and genome edited models with mutations in arrhythmogenic genes (LMNA, FLNC, DSP), and 20 age/gender/ethnicity-matched healthy individuals. Using engineered heart tissue scaffolds (EHT), we will elucidate the mechanisms of CFs activation and arrhythmia, compare altered signaling pathways in iPSC-derived models with those in the explanted hearts cohort (Aim 2), and pharmacologically rescue the phenotype.

NIH Research Projects · FY 2026 · 2023-04

The goal of this proposal is to determine the optimal time restricted eating (TRE) window to produce weight loss in adults with overweight or obesity. Daily caloric restriction (DCR), the current standard of care dietary strategy for weight loss, produces 5-7% weight loss in the context of a guidelines-based behavioral weight loss program, yet adherence is challenging and weight regain is common. Thus, rigorous evaluation of the effectiveness of novel dietary interventions is needed to provide a range of evidence-based options to effectively treat obesity. TRE involves restriction of energy intake (EI) to a limited window of time each day and has been widely promoted in the lay press, but TRE studies to date have shown only minimal (0-4%) weight loss. However, prior TRE studies have several substantial limitations, including small sample sizes, short duration, and failure to provide appropriate obesity treatment guidelines-based behavioral support. While several different dietary strategies can be used to achieve energy restriction, behavioral support is critical to enhancing adherence to both diet and physical activity (PA) recommendations and thus weight loss outcomes, yet no prior studies have provided behavioral support for TRE. Further, most TRE studies to date have utilized late TRE windows (L-TRE, e.g., eating window 12-8 PM), often providing the rationale that participants are more likely to adhere to L-TRE rather than early TRE (E-TRE, e.g. eating window 8AM-4PM). However, there is strong rationale from mechanistic studies to suggest E-TRE may result in greater weight loss and cardiometabolic benefits than L-TRE. We have shown that E-TRE results in improvements in glucose variability and insulin sensitivity, clinically significant weight loss (6.3 ± 4.1% at 12 weeks), as well as improvements in dietary quality, increased PA, reduced sedentary time and subjective improvements in sleep. However, we did not include a L-TRE control, so it is unclear whether the E-TRE window or the provision of behavioral support enhanced weight loss outcomes as compared to prior TRE studies. Thus, a rigorously designed trial is needed to evaluate the impact of E-TRE and L-TRE delivered in the context of a guidelines-based behavioral intervention on weight loss and cardiometabolic outcomes. In this study, 108 adults with overweight or obesity will be randomized 1:1 to E-TRE (8-hr window starting at 8 or 9AM, depending on habitual wake time) or L-TRE (8-hr window starting at noon or 1pm, depending on wake time) for 26 weeks (primary outcome), with follow up at 52 weeks. Our aims are to compare the effects of E-TRE and L-TRE on: 1) Changes in body weight and composition and markers of cardiometabolic health; 2) Dietary adherence, EI and dietary quality; and 3) PA and sleep. Our overall hypothesis is that E-TRE will result in greater weight loss and improvements in cardiometabolic outcomes as compared to L-TRE. In addition, we hypothesize that adherence to E-TRE and L-TRE will be similar, but E-TRE will result in greater reductions in EI, adherence to PA and improved sleep duration/quality as compared to L-TRE.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The placental precise mechanisms causing abnormal fetal growth remain to be fully established, however changes in amino acid transport may contribute to both IUGR and fetal overgrowth. The Large Neutral Amino Acid Transporter Small Subunit 1 (LAT1) mediates transplacental transfer of essential amino acids and thyroid hormones by the transporter System L. Importantly, placental System L amino acid transporter activity is decreased in human IUGR and increased in fetal overgrowth in women. However, it remains unknown if changes in the expression/activity of placental LAT1 are mechanistically linked to placental function, fetal growth and offspring cardiometabolic outcomes. Importantly, global Lat1 deletion leads to embryonic lethality in mid-gestation in mice, making it difficult to determine the role of LAT1 for placental function. Other genes, albeit not embryonically lethal, may influence both early placental development and the function of the established placenta, requiring tools to `turn-off' or `turn-on' genes at specific time points of gestation. Thus, there is an urgent need to develop approaches to achieve inducible, trophoblast-specific gene modulation. The objective of this proposal is to develop and validate novel approaches for inducible trophoblast-specific gene modulation in mice and to test the central hypothesis that restoring normal trophoblast Lat1 expression rescues the embryonic lethality of global Lat1 deletion and that trophoblast-specific Lat1 knockdown after the establishment of the placenta decreases placental transport of essential amino acids and inhibits placental mTOR, mitochondrial respiration and protein synthesis, restricts fetal growth and programs offspring metabolism and cardiovascular function. We propose three Specific Aims: Aim 1: Develop and validate mice with inducible trophoblast-specific Lat1 gene modulation. Our approach will be to generate mice with doxycycline-inducible, trophoblast-specific Lat1 gene knockdown or rescue in Lat1-/- embryos using piggyBac transposase-enhanced transgenesis, lentivirus-mediated transduction of blastocysts and tetraploid complementation assay, respectively. Aim 2: Determine the effect of trophoblast-specific Lat1 modulation on placental function, fetal growth and offspring long-term outcomes. Our approach will be to (1) induce Lat1 knockdown after the establishment of the placenta and (2) rescue trophoblast Lat1 gene expression in global Lat1 knockout (Lat1-/-) embryos. We will determine transplacental transport of amino acids and thyroid hormones, placental mTOR signaling activity, mitochondrial respiration and protein synthesis, fetal growth and offspring long-term metabolic and cardiovascular function Aim 3: Establish the effect of LAT1 modulation on primary human trophoblast syncytialization and function. Our approach will be to isolate primary human trophoblast (PHT) cells from term placentas and determine syncytialization, amino acid and thyroid hormone uptake, mTOR signaling, mitochondrial respiration and protein synthesis in control PHT cells, in PHT cell with siRNA mediated LAT1 knockdown and in PHT cells with LAT1 overexpression.

NIH Research Projects · FY 2026 · 2023-04

Abstract Craniofacial development is a complex process requiring coordinated proliferation, morphogenesis, fusion and differentiation of distinct facial prominences. The complexity of this process leaves it vulnerable to genetic and environmental perturbations, such that craniofacial malformations are a common human birth defect. Thus, about 75% of birth defects involve the head, face, and oral tissues - with orofacial clefting affecting ~1 in 700 live births. Orofacial defects such as CL/P (cleft lip with or without cleft palate) can impart a significant decrease in quality of life on those afflicted and present a major economic burden associated with treatment. The underlying genetic and developmental processes of embryonic facial development are strikingly similar in human and mouse, making the mouse one of the best available model systems to study human pathology. Despite this similarity, there are unfortunately very few cases in which the same gene mutation in mouse and human are known to cause CL/P. One notable exception is TFAP2A, the gene encoding transcription factor AP-2, which causes CL/P when mutated in mouse and is also linked to both human syndromic and non- syndromic CL/P. Notably, TFAP2A is mutated in human Branchio-Oculo-Facial Syndrome (BOFS) a monogenetic condition that presents with orofacial clefting, branchial skin anomalies, and eye defects. Previous clinical studies have indicated that missense mutations in TFAP2A generally cause more severe phenotypes than heterozygosity. Indeed, in vitro studies have shown that such missense mutations have a dominant negative mechanism of action - inhibiting DNA binding of a wild-type protein partner in the functional dimer. To study the etiology of human BOFS, we recently constructed a BOFS mouse model by conditionally placing a human missense mutation into the mouse Tfap2a locus. This humanized BOFS model recapitulates the craniofacial phenotypes observed in human patients including CL/P and branchial defects. This proposal will use this new model to test the hypothesis that CL/P caused by dominant negative BOFS mutations can be reversed by in utero treatment that alters the ratio between mutant and wild-type protein. In Aim 1 viral vectors will be used to add supplementary wild-type AP-2 early in development to titrate out the mutant protein. This approach will also be tested in related Tfap2a CL/P models in which there is insufficient AP-2 available. Aim 2 will employ anti-sense oligonucleotides to target and preferentially knockdown the mutant message in the BOFS mice. Finally, in Aim 3 a gene editing approach will be used to target the mutant BOFS allele. The expected outcome of the proposed research is a deeper understanding of delivery systems and therapeutic approaches for in utero treatments, and this should have a broad impact on how we approach human congenital dental and craniofacial disorders caused by dominant negative or loss of function mutations. Our Aims are aligned to the NIDCR RFA entitled “In utero Treatments of Congenital Dental and Craniofacial Disorders Using Precision Medicine Approaches” (RFA-DE-23-004) for which this application is targeted.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Optimal health for children with medical complexity (CMC) often depends on exposure to pediatric polypharmacy (≥5 concurrent medications). Medication-related problems (MRPs), like inappropriate therapy, undertreated symptoms, or adverse drug events, can lead to emergency visits or hospitalizations. Yet, during routine clinical care for CMC, polypharmacy is infrequently assessed and rarely managed comprehensively. To improve medication-related patient outcomes, safety, and value, a new approach is needed to manage polypharmacy in the priority population of CMC. Pharmacist-led medication therapy management (MTM) is a proven and effective tool for managing adult and geriatric polypharmacy. Our scientific premise is that a structured pharmacist-led Pediatric Medication Therapy Management (pMTM) intervention will improve the proactive management of polypharmacy by directly addressing major gaps in current practice. The implementation of pMTM to address pediatric MRPs thus represents innovation based on an established foundation. We propose a hybrid type 2 randomized controlled trial (RCT) of a pMTM intervention. This 5-year study compares the effectiveness of a pMTM intervention to usual care for reducing the primary outcome of MRPs, as well as the secondary outcomes of symptom burdens and acute healthcare utilization. In Aim 1, we use a hybrid type 2 RCT to quantitatively measure reach and effectiveness of the pMTM intervention. We will recruit CMC with polypharmacy and their parents within an academic center’s outpatient complex care program that serves >5600 CMC annually. In Aim 2, we will quantitatively and qualitatively examine important patient and parent characteristics that modify the effectiveness of the pMTM intervention. In Aim 3, we will assess adoption, implementation, and potential for maintenance of the pMTM intervention by healthcare providers, including program replication costs. The University of Colorado Anschutz Medical Campus provides a unique research environment enabling the conduct of pediatric polypharmacy research, supported by collaborative research partnerships between the Adult and Child Center for Health Outcomes Research and Delivery Science (ACCORDS), the Skaggs School of Pharmacy and Pharmaceutical Sciences, and the Children’s Hospital Colorado Special Care Clinic for children with medical complexity. Dr. James Feinstein, an expert in pediatric complex care and polypharmacy research, will lead an experienced team of co-investigators including, Dr. Allison Kempe (pragmatic trials and implementation science), Dr. Chris Feudtner (health services and complex care research), Dr. Lucas Orth (pediatric pharmacy), Dr. John Rice (biostatistics and longitudinal methods), Dr. Megan Morris (qualitative research), and Dr. Mark Gritz (economic analysis) to complete the proposed research. If pMTM is proven effective, it could be rapidly disseminated nationally as a model for pharmacist integration into outpatient complex care programs and it could have enormous impact on the public health of CMC by preventing medication-related safety issues, attendant morbidity, and associated costs.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract The overarching goals of this proposal are to contribute to the understanding of the causes, mechanisms, and potential strategies for prevention of the epidemic of chronic kidney disease of unknown origin (CKDu). Our central hypothesis is that exposure to high concentrations of airborne contaminants will be associated with kidney injury, cellular stress, and systemic inflammation in females at-risk for CKDu in Guatemala and Nicaragua. Nearly all research to date has focused on males, neglecting preliminary data showing that females working in agriculture and living in agricultural communities in Central American countries are also affected by CKDu. Additionally, studies to date have largely overlooked consideration of air pollutants as contributors to CKDu etiology. Given community pathways the potentially high exposures among Central American women from i n-home cooking sources, ambient air pollution, and agricultural sources, this is an ideal population to explore these potential linking exposure with kidney injury. In this proposal, we will characterize occupational and non- occupational airborne exposures to particulate matter (PM), silica, and metals over repeat 8-hour monitoring periods in 200 female sugarcane workers across three years (Aim 1). We will conduct 8-hour monitoring for each participant at three time points, twice during the harvest, when exposure is highest, and once during the off- season. We will evaluate the relationships between individual exposures (PM, silica, and metals) and risk factors (heat stress and dehydration), mechanisms of injury (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and uromodulin), heat-associated and cellular stress (heat shock protein 70), and inflammation (C- reactive protein, white blood cells, and cytokines), and kidney biomarkers of effect (serum creatinine and cystatin C) both acutely (Aim 2) and longitudinally (Aim 3). In addition, we will utilize novel statistical techniques, Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression and/or quantile g-computation, to estimate the effects of airborne pollutant mixtures on kidney injury and inflammation (Sub Aim 2.1). The overall goal of the study is to increase understanding of risk factors for CKDu in females to facilitate future research and prevention strategies. The proposed research addresses a knowledge gap in understudied, highly exposed populations: female workers in Guatemala and Nicaragua. The individual, and combined, contributions of exposures and risk factors on biomarkers of kidney dysfunction, cellular stress, and inflammation will be examined in this study. This exposure conducting stress, stress a) investigate an unexplored pathway to identify inhalation exposures that may place female agricultural workers at risk by a robust personal exposure assessment; b) evaluate the relationship between exposure(s), cellular inflammation, and kidney injury; and c) examine underlying mechanisms by which dehydration and heat contribute to increased risk of kidney injury. Results will lead to research will: intervention trials that will help prevent CKDu by targeting approaches for vulnerable populations that can be disseminated in the US and internationally.

NIH Research Projects · FY 2026 · 2023-03

Project Summary These studies address the large gap in knowledge regarding how commensal bacteria in the airway protect against bacterial pneumonia. Next generation sequencing studies of the airway microbiome have revealed that specific respiratory bacteria are associated with a reduced abundance of Streptococcus pneumoniae, a major cause of bacterial pneumonia, indicating a potentially protective role. A long-term goal of this work is to reduce the burden of pneumonia by optimizing protection mediated by `beneficial' airway commensals. This project will advance this goal by addressing how a prominent respiratory bacterium influences immune-mediated clearance of S. pneumoniae from the lung. For this purpose, we developed an animal model that recapitulates the relationship between one of the most abundant bacteria detected in the lung, Prevotella melaninogenica, and lung infection with S. pneumoniae. Preliminary data indicate that exposure to P. melaninogenica dramatically improves early clearance of S. pneumoniae from the lung. This effect requires neutrophils, the innate immune receptor TLR2, and the production of pro-inflammatory cytokines, including TNFα. Neutrophils purified from the lungs of P. melaninogenica-exposed mice express TLR2-dependent TNFα and are more effective at killing S. pneumoniae. Further, digestion of P. melaninogenica lipoproteins, which are recognized by TLR2, is associated with loss of protection and TNFα expression, highlighting key roles for these molecules. Finally, regulation of P. melaninogenica-induced inflammation by the anti-inflammatory cytokine IL-10 restrains the TNFα-associated inflammatory response within 24 hours and is important for effective S. pneumoniae clearance. These data support the overall hypothesis that P. melaninogenica serves complementary roles to protect against S. pneumoniae infection by 1) inducing an innate immune response characterized by TLR2-dependent activation of neutrophils, which enhances rapid clearance of S. pneumoniae from the lung, while 2) supporting IL-10 dependent abrogation of infection-associated inflammatory damage. To address this hypothesis, Aim 1 investigates host factors required for enhanced S. pneumoniae killing, including alveolar macrophages, neutrophil TNFα signaling, and baseline immune priming by the endogenous microbiota. Aim 2 evaluates how lipoprotein-TLR2 signaling intersects with other Prevotella ligand-TLR interactions and addresses the generalizability of the protective effect by comparison with other Prevotella species. In Aim 3, lung cellular infiltration, activation and pathology will be assessed over the course of S. pneumoniae co-infection in mice with deficiencies in IL-10 or myeloid cell IL-10R to determine the kinetics and cellular targets of P. melaninogenica-induced, IL-10-mediated control of inflammation and injury. Together, these studies provide a mechanistic pathway to investigate the microbiome-lung axis in order to guide the development of new strategies to improve airway commensal-mediated protection in vulnerable populations.

NIH Research Projects · FY 2026 · 2023-03

Cardiovascular diseases such as vascular calcification are a leading cause of death in patients with chronic kidney disease (CKD). However, there is no effective therapy for vascular calcification available. Phosphotoxicity and lipototoxicity are the major causes of CKD-dependent vascular calcification. Our long-term goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our previous studies have demonstrated that stearic acid (C18:0), one of the major saturated fatty acids (SFAs), is a critical metabolite that contributes to CKD-dependent vascular calcification. Mechanistically, CKD-mediated hyperphosphatemia (high inorganic phosphate) induces the significant repression of VSMC stearoyl-CoA desaturase (SCD), which is a major enzyme that controls levels of C18:0 by converting it to oleic acid (C18:1n- 9). Accumulation of C18:0 by SCD strongly induces severe lipotoxicity in VSMCs, resulting in vascular calcification. In addition, our group has found that the pro-calcific effect of C18:0 is mediated by two major metabolites of C18:0 generated via the enzyme reaction with glycerol-3-phosphate acyltransferase-4 (GPAT4): 1) 1,2-di-stearoyl-phosphatidic acid (18:0/18:0-PA), which induces vascular calcification through the activation of the PERK-eIF2-ATF4 axis of the ER stress pathway and 2) 1-stearoyl-lysophoshatdic acid (18:0-LPA) which strongly inhibits autophagic flux through the formation of abnormal MAM-associated omegasomes, which are a platform for autophagosome formation. C18:0 induces vascular calcification through the activation of the ER stress response and the inhibition of autophagy. However, the molecular mechanism underlying the upstream event in which CKD-mediated hyperphosphatemia transcriptionally represses VSMC SCD has not been studied. We believe that the identification of the mechanism has therapeutic potentials. To find clues of the mechanism, we recently screened a library of chemicals that modulate epigenetics and gene transcription. Based on the epigenetic and transcriptional chemical library screening, we identified two transcriptional repressor candidates that contribute to phosphate-mediated SCD repression and vascular calcification. We therefore propose two specific aims to elucidate the upstream event in the regulation of lipotoxicity-induced vascular calcification. Aim 1 will examine whether the transcriptional repressor modulation complex affects lipotoxicity and vascular calcification by altering SCD expression in cultured cells. Aim 2 will examine whether modulation of transcriptional repressors affects phosphotoxicity, lipotoxicity and vascular calcification in vivo. Completion of this project will provide a novel therapeutic target for CKD-mediated vascular calcification.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT During K23 funding, I will become an independent investigator focusing on the neural effects of sex steroids and their analogues as they relate to behavioral processes. My research aims to improve gonadal steroid manipulations across the female lifespan. As a critical first step, this research plan will evaluate the effect of hormonal contraception on reward processing in the brain and assess its relationship to behavioral side effects and patient utilization. Behavioral side effects of hormonal contraception such as negative mood and decreased sexual desire represent some of the most frequently cited reasons for discontinuation. Discontinuation of hormonal contraception is a known risk factor for unintended pregnancies. In order to personalize treatment that limits such side effects as well as improve tolerability of future agents, progress in steroid neuroscience is necessary. Current understanding of how hormonal contraception influences brain function has been limited by a lack of prospective controlled investigations. Utilizing a placebo-controlled design, this project will be the first to elucidate how a common oral contraceptive agent containing ethynyl estradiol and levonorgestrel (EE/LNG) influences brain reward function via both neuroimaging and behavioral assessment. This research will reveal how EE/LNG affects ecologically relevant behaviors (i.e., motivation, sexual function) in reproductive women, and serve as the basis for investigation of other steroid contraceptive agents on these processes. My research background in behavioral neuroscience combined with my clinical interests in women’s behavioral health eventually led to my current focus in psychoneuroendocrinology. Now, as an Assistant Professor at the University of Colorado Anschutz Medical Campus (CU-AMC), I have significant support and resources to train to independence utilizing the K23 mechanism. My mentorship team is led by C. Neill Epperson, M.D. and includes experts in neuroimaging (Drs. Tregellas and Epperson), sex steroids (Drs. Epperson and Santoro), and statistical modeling (Dr. Sammel). My training objectives include deepening my understanding of: 1) neurobehavioral effects of sex steroids; 2) advanced techniques in neuroimaging and 3) clinical trials and statistical modeling. I will also 4) improve my research collaborating, writing and presentation skills and 5) obtain additional training in the responsible conduct of research. I will accomplish these training objectives through coursework and seminars, guidance from mentors/consultants, and completion of the proposed research.

NIH Research Projects · FY 2026 · 2023-03

Youth-onset type 2 diabetes (YO-T2D) is increasingly prevalent in parallel with the obesity epidemic, yet effective treatment and prevention strategies are limited. The physiologic increase in insulin resistance occurring during puberty, in combination with obesity-related insulin resistance, enhances the risk of T2D. Yet, it remains unclear why some youth progress through puberty with intact β-cell function, while others do not, despite similar phenotypic and metabolic characteristics. More information is needed regarding the unique events during puberty to better understand 1) the basic pathophysiology of glucose control, insulin sensitivity, β-cell function, and T2D risk in youth, 2) differences among girls and boys, populations at highest risk, and urban and rural geographies, and 3) the potential contribution of other risk factors including psychological, behavioral, and social and external contexts. Importantly, this research needs to address the timeline of pathophysiology and progression from normoglycemia or prediabetes to YO-T2D. The DISCOVERY of Risk Factors for Type 2 Diabetes in Youth (DISCOVERY) study provides a unique opportunity to characterize the risk progression profile and mechanisms underlying the development of YO-T2D, and evaluate the effects of modifiable and non-modifiable risk factors. Ultimately, the results of this study will establish a basic pathophysiology to inform future studies aimed at achieving target glycemia, improving insulin sensitivity, preserving β-cell function, and/or preventing YO-T2D. To address this goal, DISCOVERY will recruit, enroll, and follow a nationally-representative cohort of 3,600 at-risk obese youth in early puberty; extensively phenotype them as they transition through puberty; and characterize the course of decline and dysfunction in pathophysiological indicators that lead to YO-T2D. The expected duration of the DISCOVERY is 5 years, including planning, recruitment, follow-up, analysis, and reporting. In addition, DISCOVERY will store longitudinal biospecimens and genetic material with the intention of acquiring additional ancillary funding to pursue analysis of emerging indicators. University of Colorado has experience in multicenter and diabetes-related investigations, including the TODAY, SEARCH and RISE studies, and will contribute to DISCOVERY through the recruitment of approximately 240 at-risk youth, implementation of the IRB-approved consensus protocol, participation on DISCOVERY committees, and collaboration on the analyses and dissemination of the findings from DISCOVERY. The two primary sites of recruitment will allow for a recruitment of a diverse participant cohort: Children’s Hospital Colorado has a large obesity treatment program with a wide catchment area that includes both urban and rural patient populations; Denver Health is a safety net health network that primarily serves an urban population with a disproportionately high risk for T2D. We anticipate that more than 50% will identify as Hispanic or Latino and will have a strong family history of diabetes.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY The overarching objective of this proposal is to determine if transfemoral osseointegrated prostheses have a positive influence on the etiology of hip osteoarthritis (OA). The two leading causes of disability following transfemoral amputation are chronic skin pathologies due to poor socket fit (e.g., ulceration) and OA due to habitually altered joint loading. Osseointegrated prostheses are a recent clinical intervention to treat socket related pathologies by directly mounting the prosthesis to the residual limb through a bone anchored implant, providing a more normative load transmission from the ground to residual limb. This proposal will determine if this improved load transmission has positive role on the pathogenesis of hip OA differently than socket prostheses. This will be accomplished through a longitudinal study design that will compare the most common biomechanical etiological factors to OA progression at two timepoints (baseline and 12-months) between two groups (patients with osseointegrated prostheses and patients who successfully use a traditional socket prosthesis). In Aim 1, we will quantify bilateral hip muscle quality using fat fraction quantitative magnetic resonance imaging (MRI). Using these images, we will quantify 3D muscle volume and levels of fatty infiltration on the bilateral hip musculature. This will elucidate if the known atrophy and poor composition due to disuse in a socket prosthesis, both of which are known to progress OA, can be reversed following prosthesis osseointegration. In Aim 2, we will quantify dynamic cartilage loading mechanics using motion capture and a subject-specific musculoskeletal contact model. Because altered cartilage loading is a primary instigator and factor in OA onset and progression, these results will determine if cartilage mechanics are normalized during activities of daily living following osseointegration. Although muscle composition and cartilage mechanics are etiological factors to OA development, we seek to assess the role of osseointegration on the clinical progression of OA. Thus, in Aim 3, we will quantify cartilage health using T2 quantitative MRI, which is currently the most sensitive methodology to assess early osteoarthritic changes in-vivo. Ultimately, we seek to use our multi-domain approach to better inform targeted interventions aimed at improving outcomes following osseointegration. The candidate’s overarching career goal is to utilize engineering-based tools to better elucidate the mechanisms to secondary pain conditions that can be used to improve targeted interventions. This proposal builds on the candidate’s current expertise by providing new training in quantitative MRI, advanced imaging post- processing tools, longitudinal research design and implementation, and links between biomechanics and clinical factors of joint disease. The mentoring team consists of physical therapists, radiologists, bioengineers, and orthopaedic surgeons who are experts in imaging, clinical interventions, and OA. This proposal will provide preliminary data for an R01 focused on key factors that affect long-term outcomes with varying prosthesis types.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Infants who are hard-of-hearing (IHH) are at significantly increased risk for poor auditory development and speech perception (e.g., perceiving cat versus hat), despite early hearing detection and intervention. For infants with normal hearing (INH), the first year of life is a seminal period for refining speech perception abilities shaped by exposure to language. During this early developmental period, perceptual skills become more narrowly tuned to spectral and temporal features, or cues, that favor discrimination of behaviorally relevant information. Thus, early perceptual skill development is driven by the dynamic interplay between language experiences and the concurrent maturation of auditory sensory pathways. Because refinement of speech discrimination abilities depends on an infant's exposure to speech sounds, IHH are susceptible to atypical development during this period. What remains poorly understood is the impact of inconsistent auditory cue access and poor speech perception among IHH. There is a critical need to map auditory development among IHH and to understand the long-term impacts of auditory cue processing on speech perception abilities. Filling this need will lay the foundation for developing clinical tools that will aid in personalization of intervention strategies. Our overall objectives in this application are to 1) map the emergence of speech perception among IHH compared to a cohort of age-matched INH; 2) describe the effects of auditory speech cue access on speech discrimination in noise, and 3) to assess the relationship between attunement of speech perception and functional auditory skills. By comparing these groups at 3, 6, and 12 months of age, we can describe the extent to which maturation and experience contribute to the emergence and attunement of speech perception abilities. To document speech perception development, we will use scalp-recorded electroencephalography (EEG) measured in response to native and non-native speech sounds. Our hypotheses are: 1) INH will demonstrate attunement for vowel and consonant speech sounds, but IHH will not; 2) speech perception abilities measured at 12 months of age will be positively correlated with discrimination abilities; and 3) auditory development scores will be higher for infants who demonstrate attunement to English consonant sounds. Results will inform our understanding of speech perception and auditory skill development among IHH. Our long-term goal is to improve speech and language outcomes in children with hearing loss. This project is relevant to NIDCD's mission of understanding the mechanisms of hearing loss which impact the emergence of speech perception and functional auditory skill development.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY The colon is a responsive tissue, and the epithelium replaces itself every 3-4 days. The colon has dedicated stem cells that divide for self-renewal and differentiation into specialized cell types. Differentiated colon cells perform distinct functions including water absorption and mucus secretion. In many tissues, differentiation is driven by epigenetic mechanisms including histone modifications. Methylation of histone H3 at lysine 36 (H3K36) is associated with gene bodies at sites of transcriptional activity. H3K36 methylation contributes to differentiation and stem cell maintenance in rapidly renewing tissues including blood and testes. Based on preliminary data, I hypothesize that H3K36 methylation governs cell fate decisions and reinforces cell identity in colon epithelial cells, specifically colonocyte and goblet cell lineages. To address this hypothesis, I will pursue two specific aims. First, I plan to characterize the H3K36 methylation signature in colon epithelial cells. Second, I will determine the functional role of H3K36 methylation in colon cell identity. Although, establishing a direct connection between specific histone modifications and cellular processes is challenging due to redundancies in the system, I can overcome this obstacle by taking advantage of a lysine (K)-to-methionine (M) mutation first discovered in cancer patients to precisely suppress H3K36 methylation. I will combine multiple cutting-edge tools to specifically trace and manipulate H3K36 methylation in mice and organoid model systems to advance the understanding of chromatin and lineage specification in the colon. I will also utilize novel sorting protocols to purify distinct colon cell populations for comparative epigenetic and transcriptional analysis. Collectively, this work is significant because it will establish the role of H3K36 methylation in controlling cell-type specific gene expression and lineage decisions in the colon. Revealing the role histone modifications play in colon homeostasis is the first step to understanding how these regulatory mechanisms break down in diseases such as colitis/cancer and could impact human health.

NIH Research Projects · FY 2026 · 2023-03

Project summary Children with craniosynostosis typically undergo surgical treatment to remove the brain growth constraints and correct for the malformations produced a volume overgrowth parallel to the fused sutures that compensates for the local growth restrictions. However, there is a large variability of surgical techniques and outcomes among institutions, and it is common for patients with suboptimal treatments to require additional invasive surgeries for three main reasons: (1) local volume anomalies and their progression have not been characterized to estimate how much local volume patients need during treatment; (2) our knowledge about how treatment modifies cranial growth is limited and post-surgical growth predictions are not possible; and (3) there are no objective and personalized methods to evaluate long-term outcomes, so treatment selection remains subjective. Although our team and others have created methods to quantify cranial and head shape anomalies using imaging data, existing methods cannot characterize the abnormal patterns of local volume development in craniosynostosis, are age-agnostic, and do not account for sex, which is an essential modulator of development. Moreover, our recently created data-driven normative cranial bone development model cannot be used to predict growth of a surgically modified cranium, and large post-surgical datasets have not been traditionally available to characterize volume development after treatment of patients with craniosynostosis. This limited knowledge about the abnormal pre- and post-surgical local volume development has hindered the translation of existing methods to plan, quantify, compare and predict surgical outcomes. Hence, treatment selection remains subjective and the identification of relapsing patients still relies on subjective interpretation of variable clinical symptoms with low predictive value. We demonstrated that CT and 3D photogrammetry provide the same quantification of head anatomy, and Children’s Hospital Colorado incorporated pre- and post-surgical 3D photogrammetry acquisition in the standard clinical protocol of patients with craniosynostosis. In this project, we will leverage our retrospective dataset to characterize local head volume development in patients with craniosynostosis before surgery, study how treatment modifies growth patterns and identify relapsing patients using objective data. The main goals of this project are: (1) to quantitatively characterize the local head volume distributions and their temporal progression in patients with craniosynostosis; and (2) to predict and evaluate local head volume growth after treatment of craniosynostosis. This project will create the necessary objective and quantitative knowledge to achieve personalized optimal treatments, and software tools to objectively evaluate patients using non-invasive 3D photogrammetry before and after surgical treatment.

NIH Research Projects · FY 2026 · 2023-03

(<30 lines) Youth-onset type 2 diabetes (YO-T2D) is increasingly prevalent in parallel with the obesity epidemic, yet effective treatment and prevention strategies are limited. The physiologic increase in insulin resistance occurring during puberty, in combination with obesity-related insulin resistance, enhances the risk of T2D. Yet, it remains unclear why some youth progress through puberty with intact β-cell function, while others do not, despite similar phenotypic and metabolic characteristics. More information is needed regarding the unique events during puberty to better understand 1) the basic pathophysiology of glucose control, insulin sensitivity, β-cell function, and T2D risk in youth, 2) differences among girls and boys, populations at highest risk, and urban and rural geographies, and 3) the potential contribution of other risk factors including psychological, behavioral, and social and external contexts. Importantly, this research needs to address the timeline of pathophysiology and progression from normoglycemia or prediabetes to YO-T2D. The DISCOVERY of Risk Factors for Type 2 Diabetes in Youth (DISCOVERY) study provides a unique opportunity to characterize the risk progression profile and mechanisms underlying the development of YO-T2D, and evaluate the effects of modifiable and non-modifiable risk factors. Ultimately, the results of this study will establish a basic pathophysiology to inform future studies aimed at achieving target glycemia, improving insulin sensitivity, preserving β-cell function, and/or preventing YO-T2D. To address this goal, DISCOVERY will recruit, enroll, and follow a nationally-representative cohort of 3,600 at-risk obese youth in early puberty; extensively phenotype them as they transition through puberty; and characterize the course of decline and dysfunction in pathophysiological indicators that lead to YO-T2D. The expected duration of the DISCOVERY is 5 years, including planning, recruitment, follow-up, analysis, and reporting. In addition, DISCOVERY will store longitudinal biospecimens and genetic material with the intention of acquiring additional ancillary funding to pursue analysis of emerging indicators. The University of Colorado | Navajo-Shiprock Site and the Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center have over 15 years of experience in multicenter and diabetes-related investigations and will contribute to DISCOVERY through the recruitment of approximately 240 at-risk youth, implementation of the IRB-approved consensus protocol, participation on DISCOVERY committees, and collaboration on the analyses and dissemination of the findings from DISCOVERY.

NIH Research Projects · FY 2026 · 2023-02

Project Summary Alcohol consumption contributes to approximately 6% of worldwide deaths and is a major cause of morbidity and mortality within the United States. These statistics support a pressing need for understanding the biochemical mechanisms underlying alcohol toxicity and the pathogenesis of alcohol-associated liver disease (ALD). Chronic alcohol metabolism impacts numerous cellular pathways including glycolysis, lipid metabolism, the TCA cycle as well as antioxidant and inflammatory responses. There is a known biochemical link between metabolic alterations, oxidative stress, and protein thiol redox switches (e.g., cysteine (Cys) residues); however, very little information exists regarding how chronic alcohol metabolism impacts hepatic thiol redox signaling and control networks. Our preliminary data supports the notion that alcohol metabolism, protein acetylation, and Cys redox are highly associated. Therefore, we present an innovative approach for investigating how alcohol metabolism impacts thiol redox signaling and control. Central to our aims, the thiol redox proteome is an adaptive interface that provides a means to sense, avoid, and defend against oxidants and other toxicants. Therefore, the hypothesis of this proposal is that alcohol metabolism impacts thiol redox signaling and control through lysine acetylation, resulting in hepatic dyshomeostasis and contributing to ALD. We will investigate the proposed specific aims to test our hypothesis: Specific Aim 1: Characterize altered thiol redox signaling and control due to alcohol metabolism. Specific Aim 2: Utilize Sirtuin 1 overexpression to define mechanisms of acetylation-redox signaling and control. Specific Aim 3: Integrate mechanisms of redox- Cys and acetyl-Lys to elucidate CoAlation specific redox signaling. We will execute these research aims utilizing a cutting-edge proteomics and bioinformatics approach to reveal novel redox sensing mechanisms within hepatocytes. Elucidating how alcohol metabolism alters hepatic redox signaling and control through novel post-translational modifications will support the development of targeted clinical interventions to ameliorate ALD in millions of Americans.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Pediatric musculoskeletal infections (MSKIs) are burdensome disorders that consume significant hospital re- sources and require prompt antimicrobial treatment to prevent systemic morbidity and life-altering disability. Identifying the causative bacterial culprit for MSKIs improves care by quickly targeting therapy. However, many children suffering from MSKIs never have their bacterial cause identified using existing microbiological tech- niques. Blood cultures are minimally invasive and inexpensive but only find the pathogen in 30-50% of MSKIs. Surgically-collected biopsies of infected musculoskeletal specimens (i.e., “source cultures”) increase diagnostic yield by 30% but require invasive and expensive diagnostic procedures with potential harm from sedation and surgery. Studies are needed to identify the optimal diagnostic strategy for MSKIs (i.e., routine use of invasive procedures versus blood culture alone). The Pediatric Health Information System (PHIS) database contains administrative data from millions of inpatient encounters and could be leveraged to efficiently study the diag- nostic variability for MSKIs at 52 pediatric hospitals in the United States. In addition, new diagnostic modalities have emerged that hold promise for pediatric MSKIs but need further study in these patients. Specifically, next- generation sequencing of microbial cell-free DNA (mcfDNA) from a peripheral blood specimen is a newly de- veloped non-invasive diagnostic test that uses a “liquid biopsy” to detect more than 1000 potential pathogens. Although mcfDNA testing is approved for clinical use, this test has not been validated in children with MSKIs specifically. The lack of evidence for how mcfDNA compares to invasive diagnostic procedures limits its clinical utility in this population. The Infectious Diseases Society of America (IDSA) recently called for new studies to determine whether mcfDNA testing could improve care for pediatric MSKIs. In addition, mcfDNA has an esti- mated cost of more than $2000, and cost analyses are needed to justify its use. This proposal aims to address the critical need for an optimized diagnostic strategy in pediatric MSKIs by (1) describing national variability in diagnostic testing and associated clinical outcomes for acute pediatric MSKIs; (2) determining the clinical performance of non-invasive mcfDNA testing for MSKIs compared to microbiological testing of surgically collected bone and joint specimens; (3) describe the cost of mcfDNA as compared to existing diagnostic options for pediatric MSKIs. This project is the culmination of this candidate’s dedication to improving clinical outcomes for children hospitalized with MSKIs. The objective of this award is for the candidate to develop the skills needed to meet his long-term goal of becoming an independent investigator studying diagnostic innovation for pediatric infections. The candidate will build on his research skillset through expert mentorship, didactic coursework, and experiential training in diagnostic trials and descriptive cost analyses. The candidate has thoughtfully assembled a multidisciplinary mentorship team with extensive expertise in the above aims to help him successfully complete his career training goals and research specific aims.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Cancer screening is an essential cancer control strategy for several cancer types, including colorectal, cervical, and lung cancer screening. However, cancer screening utilization rates are suboptimal and disparities by race and ethnicity persist. Observed disparities in cervical, colorectal, and lung cancer screening by race and ethnicity likely contribute to the persistent and historic disparities in survival for these cancers. Prior research and theoretical models indicate that multilevel (e.g., patient-, provider-, healthcare system-level) cancer screening initiatives are the most effective for improving outcomes and understanding modifiable drivers of disparities. However, such initiatives have been difficult to implement given the paucity of research on healthcare system- level factors, including how factors at the healthcare system-level intersect with those at the other levels. Improving utilization of cancer screening is critical to achieve population-level mortality reduction, but care must be taken to tailor interventions to underserved populations in order to ensure that existing disparities are narrowed, rather than widened. The objective of the proposed research is to improve understanding of the synergistic effects of patient-, provider-, and healthcare system-level factors on cancer screening rates, and how these multilevel factors modify racial and ethnic disparities. My specific aims are: 1) Assess cervical, colorectal, and lung cancer screening rates by healthcare system-level factors (e.g., screening policies and programs), and compare the magnitude of any observed disparities by race and ethnicity across different healthcare system- level factors (K99), 2) Characterize patient and provider perspectives on multilevel factors throughout the lung screening process using qualitative interviewing and thematic analysis (K99), and 3) Elucidate provider-level drivers of cervical, colorectal, and lung cancer screening and employ a multilevel approach to examine associations with cancer screening rates, including interactions with race and ethnicity (R00). To achieve these aims, data from the National Cancer Institute’s Population-based Research to Optimize the Screening Process (PROSPR II) consortium will be leveraged, which is unique, rich data comprised of a racially and ethnically diverse population receiving care at community healthcare systems across the US. The results of this analysis will provide evidence for the identification of potential targets for a multilevel intervention to improve screening utilization and narrow disparities. In addition to this research, Dr. Del Vecchio’s comprehensive career development plan includes structured mentorship from leaders in cancer screening research and additional training in qualitative and mixed methods research, healthcare delivery research, health disparities research, implementation science, and multilevel analysis. Throughout this award, Dr. Del Vecchio will acquire the knowledge, skills, and experience necessary to achieve her long-term goal of becoming an independent investigator studying factors contributing to suboptimal care throughout the cancer control continuum and developing multilevel interventions to improve healthcare delivery and cancer outcomes.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Metabolic and bariatric surgery (MBS) to treat pediatric severe obesity is increasingly common. MBS at younger ages means decades longer to preserve or enhance its cardiometabolic and other health benefits. While mean weight loss after MBS is substantial, >50% of adolescents in prospective US cohorts have persistent severe obesity >3 years later. We have also found that 25% of youth show significant weight regain 6 months through 5 years postoperatively. Additionally, comorbidity response to MBS appears to differ between youth and adults. In youth, few predictors of weight loss after MBS are known and there is insufficient mechanistic data evaluating physiologic factors as potential predictors. Further, there is an absence of in-depth cardiometabolic phenotyping, which could help to define residual risk post MBS beyond weight loss alone. We hypothesize that 1) physiologic phenotypes in gut peptides, body composition, and resting metabolic rate (RMR) will partially explain variability in MBS weight loss in adolescents (Aim 1), that improved insulin sensitivity (IS) will be associated with favorable cardiovascular changes independent of BMI change (Aim 2), and 2) Adjunctive postoperative glucagon-like peptide-1 (GLP-1) pharmacotherapy will augment MBS benefits in youth with suboptimal surgical response. I propose a 2-phase design: a 1-year prospective study measuring changes in gut peptides, body composition, RMR, and cardiometabolic measures (IS, 24 hour blood pressure, echocardiogram for structure/function, arterial stiffness, cardiac autonomic function) from pre- to 1 year post-MBS (n=30), 2) A randomized, double-blinded, 6- month intervention of semaglutide vs placebo 1-2 years postop in 12-24 year olds with <20% BMI loss (n=18). As an Assistant Professor in the Department of Pediatrics Section of Nutrition with a solid publication and grant funding record, and emerging clinical trial experience, I am establishing myself within the field of personalized pediatric obesity medicine. I envision future diagnostic tools and interventions for weight management in youth that are tailored to an individual’s underlying (patho)physiology, values, and socioenvironmental influences. A K23 would support the following research goals: 1) define physiologic phenotypes underlying MBS mechanism and cardiometabolic response using robust measures not previously reported in youth, 2) complete the first randomized controlled trial of a GLP-1 receptor agonist in youth post-MBS, and 3) contribute data from a diverse cohort that particularly fills gaps in under-represented Hispanic youth. My career development plan is carefully constructed to 1) learn how to longitudinally perform and interpret core dynamic measures of gut peptides, body composition, energy balance, insulin sensitivity, and cardiovascular health. Experience with these measures will yield a versatile toolbox that will be highly translatable to future clinical intervention trials in pediatric obesity. 2) gain experience with recruitment/retention for a longer study protocol (18 months), and 3) learn how traditional study designs can inform more nimble adaptive clinical trial interventions for a subsequent R01.

NIH Research Projects · FY 2025 · 2023-02

Project Summary Individuals with damage to the cerebellum exhibit debilitating deficits in motor coordination, characterized by oscillatory movements around an endpoint. The anterior interposed nucleus (IntA) is one of the main output structures from the cerebellum, with inactivation of IntA resulting in dysmetria and an instability of reaching movements. Recent findings from the lab have revealed the role of IntA as a controller of reach endpoints, facilitating precise limb movements through adaptive scaling of firing rate. While considerable progress has been made in understanding the role of the cerebellum in motor control, many questions remain concerning the signals encoded within IntA neurons during limb movement and how they contribute to the production of coordinated movements. Investigating the firing rate code of IntA neurons during complex motor tasks will help to elucidate the role of the cerebellum in anticipatory control and motor learning. To address this gap in knowledge, this proposal utilizes novel behavioral paradigms for skilled reaching in mice, cell type specific in vivo recordings during behavior, and causal optogenetic manipulations of cerebellar output. I will first determine how IntA activity is modulated to ensure endpoint precision to different targets. To do so, I will examine IntA neural dynamics, both in magnitude and timing, and their relationship to key kinematic parameters of reach precision. Secondly, I will test whether the anticipatory control signals of IntA can adapt to account for reach perturbations. Spanning circuit and behavioral levels, this proposal aims to understand the role of cerebellar output in anticipatory motor control for coordinated movement.

NIH Research Projects · FY 2025 · 2023-01

ABSTRACT Unhealthful diet is a leading risk factor for diabetes and mortality worldwide. As the diabetes and obesity epidemics continue to rise, so does the contribution of dietary risk factors to global disease burden. There is an urgent need to identify which aspects of diet causally influence metabolic disease to guide more effective dietary recommendations. Teasing apart correlation from causation remains a challenge, and while numerous epidemiological studies have observationally linked diet to diabetes, there has been limited success with translation to intervention studies. Normal human genetic variation has both direct and indirect effects on dietary intake, with recent work establishing significant heritability and hundreds of genetic associations with numerous different foods and dietary patterns. However, combining dietary traits across studies for genetic analysis remains a challenge due to study differences in design, cultures, and preferences. We hypothesize shared genetic influences on dietary intake can act as the common reference to identify comparable diets across studies. In each of several cohorts, with both genetic and diet data, we will initiate new collaborations, derive quantitative food traits and dietary patterns, and conduct genome-wide association studies (GWAS) to create homologous GWAS datasets with study-specific dietary phenotypes and a common set of genetic markers. A series of genetic correlation analyses will be conducted to identify comparable foods and dietary patterns across diverse studies. Once identified, GWAS meta-analysis of comparable dietary phenotypes will improve power to detect novel and multi-ethnic genetic associations. To elucidate the direct and indirect genetic mechanisms of dietary intake at the locus and genome-wide levels we will conduct fine-mapping and gene prioritization, enrichment and pathway analysis, and genetic correlation and phenome-wide association studies (PheWAS). To address limitations with observational studies, Mendelian randomization (MR) causal inference will be performed using genetically predicted dietary intake and publicly available GWAS on diabetes-related outcomes to prioritize causal associations for intervention trials. Clustering of genetic loci by phenotypic correlations and causal effects will pinpoint genetic mechanisms of diet that causally influence metabolic disease. We will extend MR to all UK Biobank outcomes to map comprehensive causal bidirectional relationships with diet. Overall we will identify novel and multi-ethnic genetic associations with comparable dietary phenotypes across diverse studies to elucidate the mechanisms of dietary intake and uncover causal relationships between diet, diabetes, and overall human health. To achieve my goal of becoming an independent investigator in nutrigenomic and metabolic disease research, I have designed a detailed K99 plan with didactic coursework and co-mentoring by Drs. Florez, Hirschhorn, and Willett in metabolism, statistical genetics, and nutritional epidemiology. During the R00 phase, while conducting independent research and continuing to develop research skills, I will maintain and cultivate collaborations in nutrition and genetics and grow my research program.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY The ability to integrate color and form into coherent visual scenes is an important part of our interactions with the environment. This ability is impaired in many ophthalmologic and neuropsychiatric disorders, yet the neural mechanisms responsible for visual feature integration remain understudied. The use of mice as a model organism has provided deep insights into fundamental mechanisms of vison conserved across species and general principles of neural information processing. Recent work in mice has shown that the early mouse visual system is wired to respond to chromatic information and mice can use this information to guide behavior. However, it is unclear how the early visual system integrates spectral and luminance contrasts to represent color spatially. My own preliminary data has demonstrated that neurons in mouse primary visual cortex (V1) can respond to spatial luminance contrast (i.e., form) in a color-dependent manner, building on work demonstrating responses to color contrast in in the lateral geniculate nucleus of the thalamus (LGN) – the preceding stage of visual hierarchy. This suggests that color and form begin their integration through thalamocortical networks, though the exact mechanism of integration is unknown. Thus, the goal of this proposal is to ask how, neurally, are variations in color and luminance integrated to generate spatial chromatic contrast? To do this, I will need to measure responses from a large number of neurons in LGN and V1 to capture the breadth of chromatic responses and relevant connections between regions. Leveraging the relative scale of the mouse visual system and high-density electrophysiology, this project will examine mechanisms of spatial chromatic integration with a high degree of spatiotemporal resolution. Aim 1 will examine the functional convergence of chromatic and achromatic signals from LGN to produce chromatic selectivity in V1. Aim 2 will then examine if and how intracortical networks enhance chromatic selectivity to refine color tuning for subsequent stages of visual processing. In sum, this proposal will expand our fundamental understanding of how the early visual system integrates color and luminance spatially, providing a steppingstone to further experiments investigating how color integrates with specific visual features such as orientation, direction, motion, and ultimately how color is integrated into complex naturalistic scenes. This work will also provide the applicant with invaluable training in his future career as a neuropsychiatrist focused on translating foundational knowledge from computational neuroscience into novel, highly precise therapeutics.

NIH Research Projects · FY 2026 · 2023-01

Project Summary/Abstract Background: Children with single ventricle heart disease (SVHD) experience significant morbidity due to inadequate pulmonary blood flow from insufficient pulmonary vascular development. Options to diagnose and treat this pathologic pulmonary vascular development remain limited. Endothelin-1 (ET1) and both arginine/nitric oxide (NO) and tryptophan metabolites have been linked to pathologic pulmonary vascular development. Preliminary data from our group demonstrate alterations in circulating ET1, arginine metabolites, and tryptophan metabolites at the time of Stage 2 palliation. Persistence of these pathway abnormalities between Stage 2 and Stage 3 palliation and their association with outcomes have not been studied. Hypothesis: Increased ET1 and dysregulation of the arginine/NO and tryptophan pathways in SVHD patients undergoing staged palliation disrupts pulmonary vascular development, leading to decreased pulmonary blood flow, worsened hypoxemia, and cardiorespiratory morbidities during the critical pre-Stage 3 growth years, the immediate post-operative period, and throughout childhood. Aims: Quantify serum concentrations of ET1, arginine/NO metabolites, and tryptophan metabolites in SVHD subjects immediately prior to and following both Stage 2 and Stage 3 palliation, and at the time of post-Fontan cardiac MRI to: 1) determine the association between biomarker abnormalities at Stage 2, persistent pathway changes at Stage 3, and pulmonary vascular growth by Stage 3, 2) evaluate the association between biomarker abnormalities at Stage 3, pulmonary vascular adequacy for the Stage 3 operation, and post-operative complications, and 3) determine the relationship between a pro-angiogenic metabolic signature, changes in aorto-pulmonary collateral burden, and altered pulmonary arterial flow dynamics before and after Stage 3. Methods: Longitudinal, prospective cohort study in children undergoing staged SVHD palliation combined with a cross-sectional study of older SVHD patients. Impact: 1) First longitudinal study of ET1 exposure early in SVHD palliation to support future development of ET1 as a clinical diagnostic test and biomarker-directed clinical trials of ET1 receptor antagonist. 2) First comprehensive pathway mapping of arginine/NO and tryptophan metabolism as markers of pathologic pulmonary vascular development in CHD. 3) Novel metabolomic approach to understanding AP collateral phenotype and identification of new markers of disease/potential therapeutic targets. Career Development: The proposed study will allow me to gain the data, skills, experience, and publications needed to support my transition to independent research. I will augment this with a Master of Science degree in the Clinical Sciences (MSCS) specifically targeting advanced data analysis and clinical trial design. Combined, these development aims will position me to achieve my goal of becoming an R01 funded expert in pulmonary vascular development in children with congenital heart disease.