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Principal Investigator: Karla Fitzgerald Leavens
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $113,726
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
In order for the b-cell to precisely secrete insulin in response to glucose, glucose metabolism to ATP is
tightly coupled to insulin secretion through the ATP-sensitive K (KATP) channel. Any disruption along this
pathway leads to b-cell dysfunction and ensuing diabetes or, more rarely, congenital hyperinsulinism. While
these diseases mostly arise from multiple factors, some cases are caused by single gene mutations, termed
monogenic diseases. Interestingly, the same loss-of-function heterozygous mutations in the transcription factor
HNF1a can result in both hyperinsulinism and diabetes, though presenting at different ages and through
unknown mechanisms. In the proposed project, we will investigate the underlying causes of both HNF1a-
related diabetes and hyperinsulinism. Our prior published work and additional preliminary data show that
HNF1A-deficient human stem cell-derived β-cells exhibit increased basal and decreased glucose-stimulated
insulin secretion, recapitulating the clinical disease. HNF1A-deficient β-cell models exhibited significantly
decreased glycolysis, suggesting decreased ATP production in response to glucose. Expression analyses
revealed broad defects in HNF1A-deficient β-cells in genes regulating cellular metabolism and decreased
expression of KATP channel genes. Based on these previous findings, we hypothesize that HNF1a regulates
both KATP channel expression and ATP production in response to glucose. Loss of HNF1a leads to uncoupling
of glucose metabolism and insulin secretion at these two points in the insulin secretion cascade, impacting
basal and stimulated insulin secretion in opposing directions and resulting in hyperinsulinism and diabetes,
respectively. Using a novel and manipulatable human b-cell model system combined with a variety of analytical
techniques, we will rigorously test our hypotheses and advance our knowledge of b-cell dysfunction in complex
disease states.
My long-term goal is to have a basic and translational research lab that studies the diseases resulting
from pancreatic β-cell dysfunction. My proposed K08 project will help me learn new technical methods,
develop a new intellectual foundation and generate preliminary data that will be instrumental in helping me
start my own independent lab. I chose my co-mentors as they have complimentary research approaches and
varied areas of expertise. I have a career development plan which relies on my extensive mentoring
relationships, including regular interaction with my co-mentors and my advisory committee, which contains
individuals within the local and national research community with varying areas of expertise. I have developed
a plan of training which takes full advantage of the collaborative research environment at the Children’s
Hospital of Philadelphia and University of Pennsylvania School of Medicine, including participation in trainings,
seminars, and workshops to advance my knowledge base and professional skills.
Terms: <Acute><Advisory Committees><Age><Amino Acids><Applications Grants><Area><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Basal Transcription Factor><Basal transcription factor genes><Basic Research><Basic Science><Beta Cell><Biologic Models><Biological Models><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Maturation><Cell model><Cells><Cellular model><Children's Hospital><Clinical><Coenzyme II><Communities><Complex><Congenital Hyperinsulinism><Congenital hyperinsulinemia><Coupled><D-Glucose><Data><Defect><Development Plans><Dextrose><Diabetes Mellitus><Disease><Disorder><Dissociation><Down-Regulation><Dysfunction><Educational workshop><Environment><Exhibits><Foundations><Functional disorder><Future><Gene Alteration><Gene Mutation><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glucose><Glycolysis><Goals><Grant Proposals><Heterograft><Heterologous Transplantation><Heterozygote><Human><Humulin R><Hyperinsulinemia><Hyperinsulinemia Hypoglycemia of Infancy><Hyperinsulinism><Hypoglycemia of Infancy><Individual><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin deficiency><Intermediary Metabolism><Knowledge><Learning><Link><Measures><Mediator><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Mentors><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Model System><Modeling><Modern Man><Murine><Mus><Mutation><NAD phosphate><NAD(H) phosphate><NADH><NADH phosphate><NADP><NADPH><Nicotinamide-Adenine Dinucleotide Phosphate><Novolin R><Nutrient><PHHI Hypoglycemia><Pancreatic beta Cell><Pancreatic β-Cell><Pathogenesis><Pathway interactions><Patients><Pediatric Hospitals><Pennsylvania><Persistent Hyperinsulinemia Hypoglycemia of Infancy><Phase><Philadelphia><Physiopathology><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><Production><Progenitor Cells><Publications><Publishing><RNA Interference><RNA Silencing><RNAi><Regular Insulin><Regulation><Research><Role><Scientific Publication><Sequence-Specific Posttranscriptional Gene Silencing><Signal Pathway><Structure of beta Cell of islet><Task Forces><Techniques><Testing><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Translational Research><Translational Science><Triphosphopyridine Nucleotide><Universities><Work><Workshop><Xenograft><Xenograft procedure><Xenotransplantation><advisory team><ages><aminoacid><career development><diabetes><directed differentiation><driving><drug action><energy balance><experiment><experimental research><experimental study><experiments><genome editing><genome mutation><genomic editing><glucose metabolism><heterozygosity><human progenitor cell derived><human stem cell-derived><insulin secretion><knowledge base><loss of function><loss of function mutation><medical college><medical schools><monogenic disease><monogenic disorder><mutant><novel><pancreas beta cell><pancreas β cell><pancreatic b-cell><pathophysiology><pathway><response><school of medicine><single-gene disease><single-gene disorder><skills><social role><stem cells><transcription factor><translation research><translational investigation><transplant model><type 1 and type 2 diabetes><type I and type II diabetes><xeno-transplant><xeno-transplantation><β-cell><β-cells><βCell>