· 1. Deciphering the mechanistic basis of the genetic contribution to Type 2 diabetes mellitus (T2D) in Humans.
o In a hypothesis-driven systems biological approach our studies integrate variation-based human genomic analysis with in vitro functional studies to identify the biological pathways involved in the genetic susceptibility to Type 2 diabetes (T2D).
o Concurrent with our human genetic and computational analyses of gene-expression, and genotype data from a cohort of metabolically well-characterized individuals, rigorous in vitro genetic perturbation studies and cell biological studies will identify genetically regulated biological pathways/ networks that are causal determinants of altered insulin sensitivity and glucose homeostasis in adipose and muscle tissue, and will define molecular mechanisms involved in increased genetic susceptibility to T2D.
o These genetically regulated pathways serve as targets for the development of novel therapies for T2D.
PUBLICATIONS: Hum Genet (2016) 135:869–880; J Clin Endocrinol Metab, April 2016, 101(4):1455–1468; Physiol Genomics 45: 509–520, 2013.; J Clin Endocrinol Metab 96: E1308–E1313, 2011; J Clin Endocrinol Metab 96: E394–E403, 2011; Diabetes 60:1019–1029, 2011
· 2. Connecting genetic underpinnings of T2D with mechanisms, phenotypes, and environmental interactions.
o Our collaborative study with Dr. Donald McClain’s laboratory promises to connect genetic risk factors of diabetes to a defined molecular mechanism, and then link that mechanism to a known environmental risk factor for T2D, namely dietary and tissue iron levels.
o Adipocyte transferrin (TF) plays a novel role in regulating iron homeostasis in adipose tissue and affects processes in the cell that are dependent upon iron. Altering that homeostatic mechanism through genetically determined levels of TF expression interacts with environmental changes (e.g. dietary iron) in overall iron balance and may result in reduced insulin sensitivity and may increase the risk of T2D.
o The promise of developing a mechanism linking genetic polymorphism, iron, and diabetes in this project, has direct translational potential, and will reveal new insights into adipocyte biology.
· 3. Determining common and ethnically-predominant genetic regulatory mechanisms of insulin sensitivity in African Americans and European Americans.
o Identifying the molecular mechanisms underlying ethnic differences in insulin sensitivity and heterogeneity within an ancestral group will be important for understanding health disparities, and for facilitating the identification of novel drug targets to implement precision-based medical approaches to T2D.
o Comprehensive characterization of gene network connectivity in adipose and muscle tissue (a collaboration with Dr Bin Zhang, Icahn School of Medicine at Mount Sinai, NY), its regulation, and its association to glucose homeostasis phenotypes will determine the heterogeneous genetic regulatory mechanisms of insulin sensitivity in AAs and EAs, providing critical insights into the underlying early pathogenic mechanisms of T2D, and identifying target genes for future therapeutic interventions.
PUBLICATION: BMC Medical Genomics (2015) 8:4
· 4. Understanding molecular mechanisms underlying the interaction of genetic factors with dietary factors that determine metabolically healthy and unhealthy phenotypes in obese subjects.
o The goal of this project is to elucidate how dietary free fatty acids (FFAs) interact with intrinsic factors (genetic) at the molecular level to explain the observed heterogeneity of metabolic features among obese individuals.
o Our novel ex-vivo integrative genomic approach, using subcutaneous and visceral adipose tissue-derived stem cells (ASCs) from obese subjects, allows us to explore the gene-by-diet interaction at the molecular level. The ASCs will be generated from surgical samples in collaboration with Dr. Adolfo Fernandez at Department of Surgery, WFSM.
o Studies may offer key insights regarding (a) why some obese subjects have better metabolic health compared to others with a similar body mass index, and (b) how dietary FFAs interact with genetic factors at the molecular level and thus determine the metabolic phenotype of obese individuals.
o Genetic variants that are associated with transcription in response to FFAs likely alter the effect of dietary FFAs on gluco- and cardio-metabolic outcomes. This study could lead to personalized therapeutic and preventative (nutritional and lifestyle) approaches to reduce or prevent obesity-associated metabolic disorders.
PUBLICATIONS: International Journal of Obesity (2015) 39, 869–873; J. Lipid Res. 2010. 51: 2121–2131; J Clin Endocrinol Metab 93: 4532–4541,2008
· 5. Defining the role of DNA methylation in modulating transcript expression in tissues important for glucose homeostasis and for causing insulin resistance.
o Leveraging the availability of tissue samples, gene-expression, and genotype data of participants from a metabolically well-characterized African American (AA) cohort allows the quantitation of DNA-methylation levels in tissue DNA samples. This serves to identify the role of DNA-methylation in modulating expression of genes in a key tissue involved in glucose metabolism.
o This project will integrate DNA-methylation data with available gene-expression and genotype data to identify intrinsic factors involved in modulating insulin sensitivity and susceptibility to T2D in AAs, creating an essential and unique database of epigenetic regulatory factors involved in modulating insulin resistance-associated genes in AAs.
o Knowledge derived from this project will play a vital role in the development of nutritional and pharmacological agents that can modify DNA-methylation levels and modulate the risk of T2D in AAs.
PUBLICATION: Diabetes 2014;63:2901–2903
· 6. Identifying modulation of Micro RNA(miRNA) and Co-Regulated Target Transcripts in Insulin Resistance and Obesity
o Non-coding RNAs, like miRNAs, influence obesity and insulin sensitivity by modulating the expression of their target genes in adipose tissue.
o Our studies in human subjects and cell models indicate that miR-148a-3p mediated modulation of DNA. Methyltransferase 1 (DNMT1) expression is an important mechanism for adipocyte differentiation and it is likely impaired by obesogenic conditions.
o Further studies will be required to map the entire network of miRNA-mRNA interactions and alteration of DNA methylation levels in adipocyte and non-adipocytic cells involved in the dysfunction of adipose tissue during obesity.
PUBLICATION: MicroRNA, 2015, 4, 194-204
· 7. Identifying genetic variants modulating the pharmacological treatment-mediated transcriptional response, and dictating the treatment outcome in diabetes.
o We will characterize the set of SNPs associated with expression (eSNPs) and PPARg agonist-mediated transcriptional modulation (gene-drug interaction eSNPs) in tissues relevant to glucose homeostasis.
o The eSNPs we identify will be useful in stratifying populations in efficacy studies, to improve the quality of clinical decision-making and treatment options. Our approach will also help discover novel molecular mechanisms to elucidate the etiology of insulin resistance.
o This study will extend our current understanding of the genetic basis of variation in response to PPARg agonists, will improve our understanding of individual-level variability in drug response, and will facilitate future efforts to characterize the genetics of response to other treatments including anti-inflammatory agents to treat insulin resistance and T2D.
o Provision of help in finding more effective use of existing antidiabetic agents and in the designing new drug molecules that bypass shortcomings of currently available ones may be furnished.
PUBLICATION: Pharmacogenetics and Genomics 2012, 22:484–497