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Principal Investigator: Theodore George Drivas
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $166,860
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Rare genetic defects of the primary cilium can cause a number of phenotypically-overlapping Mendelian
syndromes, known as ciliopathies. Intriguingly, many ciliopathy patients show signs of impaired glucose
homeostasis, with accumulating evidence suggesting that insulin receptor must be specifically trafficked into the
cilium to initiate insulin-dependent signaling cascades. However, we do not yet know if variants in ciliary genes
increase an individual’s risk for diabetes more generally, nor do we understand the mechanisms by which ciliary
genes might affect insulin receptor signaling to cause pathology. The goal of this proposal is to fill this gap in our
knowledge using complementary bioinformatic and cell biologic approaches. My clinical and scientific expertise
in ciliary biology and human genetics, coupled with my exciting preliminary results, rigorous research plan, and
outstanding mentorship team, provide a solid foundation for this project. In completing the proposed work,
specifically with its focus on providing me additional training in the field of bioinformatics and in lab management,
I will be perfectly poised to begin my independent academic career as a physician scientist seeking to better
understand the genetics and biology of ciliary dysfunction in human disease. I have secured the complete support
of my institution, and will benefit greatly from the unparalleled resources and mentorship available at both the
University of Pennsylvania and the Children’s Hospital of Philadelphia over the course of this award.
I hypothesize that variants in ciliary genes increase risk for diabetes by perturbing cell signaling pathways
essential to normal insulin signaling. My preliminary analyses in the UK and Penn Medicine Biobanks have
already identified numerous ciliary genes and variants significantly associated with glucose and hemoglobin A1c
levels, and demonstrate significant changes in ciliary gene expression in response to insulin. I will further
investigate these associations with two complementary sets of analyses. Specifically, I will (1) use bioinformatic
approaches in large patient datasets to identify and characterize ciliary genes and pathways that confer
increased risk for type 2 diabetes phenotypes and (2) validate these findings in cell models of disease, with a
specific focus on understanding how genetic variation in ciliary genes perturbs the ciliary transport and
downstream signaling of insulin receptor. Through the careful use of cell and molecular biologic approaches
including signaling assays, RNAseq, and live cell imaging, I will quantify differences in insulin receptor signaling
and ciliary transport of insulin receptor when individual ciliary candidate genes, identified in Aim 1, are knocked
down in cell models. The completion of the proposed work will advance our knowledge of cilium biology and
common disease genetics, open new avenues for patient risk assessment, and has the potential to identify novel
therapeutic targets for the treatment of diabetes. Additionally, the application of the methodology and paradigm
developed in this plan will undoubtedly help with the elucidation of multiple other common disease mechanisms
attributable to Mendelian disease genes and cellular processes both within and outside of the cilium.
Terms: <Address><Adult-Onset Diabetes Mellitus><Affect><Assay><Award><BMI><BMI percentile><BMI z-score><Bio-Informatics><Bioassay><Bioinformatics><Biological><Biological Assay><Biology><Body mass index><Candidate Disease Gene><Candidate Gene><Caring><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Surface Receptors><Cell model><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cellular model><Children's Hospital><Cilia><Ciliary Process><Clinic><Clinical><Code><Coding System><Complex><Coupled><D-Glucose><Data><Data Set><Development><Dextrose><Diabetes Mellitus><Diet><Disease><Disorder><Doctor of Philosophy><Drugs><Dysfunction><Electronic Health Record><Explosion><Foundations><Functional disorder><Gene Expression><Gene variant><General Population><General Public><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Diversity><Genetic Variation><Genetic defect><Genomics><Glucose><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Hemoglobin A(1)><Human Genetics><Humulin R><Impairment><Individual><Institution><Insulin><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin-Dependent Tyrosine Protein Kinase><Intracellular Communication and Signaling><Investigation><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knockout><Knowledge><Link><Maturity-Onset Diabetes Mellitus><Medication><Medicine><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Mentorship><Methodology><Microscopy><Modality><Modeling><Molecular><Mutation><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Organelles><Pathogenesis><Pathology><Pathway interactions><Patient risk><Patients><Pediatric Hospitals><Pennsylvania><Persons><Ph.D.><PhD><Pharmaceutical Preparations><Phenotype><Philadelphia><Physicians><Physiopathology><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Public Health><Quetelet index><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Regular Insulin><Research><Research Associate><Research Resources><Resources><Risk><Risk Assessment><Role><Scientist><Secure><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Solid><Stable Diabetes Mellitus><Structure of ciliary processes><Subcellular Process><Syndrome><T2 DM><T2D><T2DM><Techniques><Testing><Training><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Universities><Variant><Variation><Work><adult onset diabetes><allele variant><allelic variant><biobank><biologic><biological signal transduction><biorepository><blood glucose regulation><career><cell biology><ciliopathy><cohort><developmental><diabetes><diabetes risk><diets><disease model><disease phenotype><disorder model><drug/agent><electronic health care record><electronic health medical record><electronic health plan record><electronic health registry><electronic medical health record><genetic condition><genetic disorder><genetic variant><genome mutation><genomic variant><glucose control><glucose homeostasis><glucose regulation><hemoglobin A1c><human disease><insulin signaling><ketosis resistant diabetes><knock-down><knockdown><live cell image><live cell imaging><live cellular image><live cellular imaging><maturity onset diabetes><monogenic disease><monogenic disorder><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><pathway><phenome><post-doc><post-doctoral><post-doctoral trainee><rare allele><rare mutation><rare variant><research associates><response><single-gene disease><single-gene disorder><social role><trafficking><transcriptome sequencing><transcriptomic sequencing><type 2 DM><type II DM><type two diabetes>