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Principal Investigator: Amit Majithia
Organization: VA SAN DIEGO HEALTHCARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Insulin resistance is a major cause of type 2 diabetes (T2D), heart attacks, strokes and cancer. These chronic
metabolic diseases disproportionately affect veterans, especially black veterans. Targeting insulin resistance by
treating obesity is effective but the major clinical options, low calorie diets or bariatric surgery, are difficult to
sustain and scale for the over 40% of veterans afflicted with obesity. Thiazolidinediones (TZDs), specifically
target insulin resistance and have proven clinically effective in preventing T2D, heart attacks and strokes, but
serious side effects have limited their clinical use. New therapeutic targets to treat insulin resistance are
needed. In theory, ‘omics’ approaches such as genome wide association studies (GWAS) of surrogate
measures of insulin resistance or mining the transcriptomic response caused by weight loss/ TZD treatment
could provide a source of novel target genes, but both approaches have limitations including identifying
specific genes/mechanisms for GWAS and distinguishing correlation from causation in gene expression
studies. Importantly, existing GWAS studies contain predominantly European samples and thus bias against
genetic discovery in African ancestry individuals. Ultimately, the dozens to hundreds of genes nominated by
‘omics’ approaches must be sifted by functional investigation for biological mechanism and therapeutic
translation. Even when a potential insulin sensitizing effector gene is validated in the lab, credentialing its
relevance to human insulin sensitivity necessitates drug development and human trials, another poorly
scalable process that usually results in failure for lack of efficacy. However, the recent accumulation of genome
sequences in large, clinically characterized populations has revealed that nature has performed countless
human trials in the form of millions of naturally occurring, protein-altering genetic variants scattered throughout
almost every gene in the genome. High-throughput functional assays are the key to unlocking these
opportunities: 1) identifying novel candidate genes for insulin resistance and 2) leveraging nature’s clinical trials
for assessing therapeutic potential. In this application, we propose to utilize a newly developed massively
parallel adipocyte differentiation/ lipid accumulation assay in an integrative genomic approach to:
Aim 1: Systematically identify novel insulin resistance genes incorporating African ancestry specific genetic
discovery in the VA population and
Aim 2: Determine the clinical effect of novel insulin resistance genes on metabolic disease in humans using
data from 488,000 sequenced individuals.
This work will identify novel insulin sensitivity genes relevant to the VA population and include African
ancestry-specific genes. It will also provide critical information on the human, clinical consequence of
modulating function of selected genes to enable therapeutic translation.
Terms: <2,4-thiazolidinedione><Abnormal Assessment of Metabolism><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Affect><African ancestry><African descent><After Care><After-Treatment><Aftercare><Alleles><Allelomorphs><Apoplexy><Assay><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Bioassay><Biological><Biological Assay><Biological Markers><Blood Serum><Body Weight decreased><Body fat><Brain Vascular Accident><CD36><CD36 gene><Caloric Restriction><Calories><Cancers><Candidate Disease Gene><Candidate Gene><Cardiac infarction><Cardiovascular Diseases><Catalogs><Causality><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><Clinical><Clinical Research><Clinical Study><Clinical Treatment><Clinical Trials><Code><Coding System><Conduct Clinical Trials><Credentialing><Data><Development><Diabetes Mellitus><Diagnosis><Diet><Disease><Disorder><Dose><Epidemic><Etiology><European><Failure><Fat Cells><Fatty Liver><Fatty Tissue><Future><GP3B><GP4><GPIV><GWA study><GWAS><Gene Expression><Gene Transcription><Gene variant><General Population><General Public><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Genome engineering><Genomic approach><Genomics><Genotype><Glitazones><HUMPPARG><Health><Hepatic Disorder><Hepatic Failure><Human><Human Genetics><Humulin R><Individual><Insulin><Insulin Resistance><Intracellular Communication and Signaling><Investigation><Ketosis-Resistant Diabetes Mellitus><Laboratories><Life><Link><Lipids><Lipocytes><Liver Failure><Liver Steatosis><Liver diseases><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measures><Metabolic Diseases><Metabolic Disorder><Metabolic Studies><Metabolism Studies><Mining><Modern Man><Modernization><Mutation><Myocardial Infarct><Myocardial Infarction><NIDDM><NR1C3><Nature><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Obesity><PPARG><PPARG gene><PPARG1><PPARG2><Participant><Phenotype><Population><Process><Proteins><Publishing><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Records><Regular Insulin><SCARB3><Sampling><Series><Serum><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Source><Stable Diabetes Mellitus><Stroke><Study of serum><Subcellular Process><T2 DM><T2D><T2DM><Testing><Therapeutic><Thesaurismosis><Thiazolidinediones><Tissue Sample><Transcription><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Variant><Variation><Veterans><Weight Loss><Weight Reduction><Work><adipocyte development><adipocyte differentiation><adipose><adiposity><adult onset diabetes><allele variant><allelic variant><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><bariatric surgery><bio-markers><biobank><biologic><biologic marker><biological signal transduction><biomarker><biorepository><body weight loss><brain attack><caloric restricted><calorically restricted><calorie restricted><calorie restriction><cardiac infarct><cardiovascular disorder><catalog><causation><cell assay><cerebral vascular accident><cerebrovascular accident><clinical effect><coronary attack><coronary infarct><coronary infarction><corpulence><developmental><diabetes><diets><discover genes><disease causation><drug development><exome sequencing><exome-seq><experiment><experimental research><experimental study><experiments><fatty liver disease><functional genomics><gastric banding><gastric bypass surgery><gene discovery><gene function><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes 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druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><obesity surgery><pharmacologic><post treatment><prevent><preventing><programs><prospective><rare allele><rare mutation><rare variant><resistance gene><resistance locus><resistant gene><response><side effect><statistics><stomach stapling><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><theories><therapeutic agent development><therapeutic development><therapeutic gene><therapeutic target><thiazolidinedione><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translational therapeutics><translational therapy><trial regimen><trial treatment><type 2 DM><type II DM><type two diabetes><weight loss surgery><white adipose tissue><whole genome association analysis><whole genome association studies><whole genome association study><wt-loss><yellow adipose tissue>