Genetic Study of PP-Fold Polypeptide-Receptor Axis on Metabolic Syndrome Risk

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DESCRIPTION (provided by applicant): Candidate. My research brings together both experimental and statistical approaches to the genetic basis of human complex and polygenic diseases with particular emphasis on metabolic syndrome. After receiving my Ph.D. in genetic epidemiology from the University of Pittsburgh, I joined the Hypertension Research Lab at the University of California, San Diego in 2007 as a National Kidney Foundation (NKF) Research Fellow. I have had a productive fellowship training experience at UCSD, generating 8 publications (with 5 more in review/progress), receiving two fellowship research awards and winning the NKF's Young Investigator Award on two separate occasions (placing first both times). My short-term (5-year) goal is to acquire molecular biology skills to uncover biological mechanisms underlying trait-associated genetic variants. Furthermore, I aim to gain expertise in translational research by extending my genetic epidemiology studies into high-risk clinic-based patient populations. With the skills that I will obtain through this K01 career development grant, new insights will be generated that should improve the management of obesity and related disease risk in clinical practice. My long-term (10 years and beyond) career goal is to be an independent academic faculty member, working with an interdisciplinary research team to devise collaborative approaches to solve complex biomedical problems. More specifically, I anticipate that my broadened knowledge and skill sets will directly translate into genetic and genomic findings to improve clinical care of high-risk patient populations. This K01 award will allow me to become immersed in a rich environment where a multidisciplinary team of investigators will teach me the statistical and molecular biological skills needed to achieve my career goals. Career Development Plan. I am already well-trained in genetic techniques (small-scale gene-sequencing and genotyping), statistics, and genetic epidemiology, and already function at a skilled level at the Departments of Medicine and Psychiatry at UCSD. However, since this is only my fourth postdoctoral year, there are dimensions of expertise that I must develop in order to be competitive as an independent principal investigator - molecular/cell biology and translational research methodology. Under the direct supervision of my mentors, Dr. Ming T. Tsuang and Dr. Daniel T. O'Connor, a comprehensive training plan has been designed for my career development over the proposed five years of K01 support (2011-2016): (1) Genetic Epidemiological and Translational Research Design - this covers genetic epidemiology and statistics, exploratory translational research, fundamentals of human research project, and responsible conduct of research, and (2) Genome Technology & Molecular Biology - this covers techniques used in genome technology, bioinformatics, and molecular biology. Project Abstract. TITLE: Genetic study of PP-fold polypeptide-receptor axis on metabolic syndrome risk. The rate of obesity is rising worldwide, resulting in an increased prevalence of the metabolic syndrome (MetS). MetS is a cluster of interrelated risk factors that promote the emerging epidemic of diabetes and cardiovascular disease. Each of the clinical traits defined within MetS is influenced substantially by hereditary determination, yet the identity of genetic variation contributing to these traits and their molecular mechanisms remain elusive. Peptide YY (PYY) and Neuropeptide (NPY) are PP-fold polypeptides activating G-protein-coupled receptors, NPY1R and NPY2R, to regulate satiety, metabolism, and vasoconstriction. Plasma NPY and PYY levels associate with eating and metabolic disorders, yet precise mechanisms underlying associations are difficult to identify due to the intermixed neuronal and hormonal functions of PP-fold peptides and their ability to bind both receptors. Here we couple emerging genomic and molecular biology techniques with a 3-tier association study design to tackle the role of the PP-fold polypeptide-receptor pathway in obesity and MetS risk. We have three Specific Aims: (1) Genetic association in vivo: Assess the role of rare (unusual) versus common genetic variants in the PP-fold peptide pathway, (2) Molecular biology: Determine the functional role of the risk alleles by in vitro approaches, (3) Exploratory translational study: Characterize the role of plasma PYY in obesity and MetS risk after atypical antipsychotic (ATAP) treatment, and assess ATAP effects on PYY pathway signal transduction in vitro. This interdisciplinary proposal bridges molecular genetics and genetic epidemiology with molecular biology studies to improve our understanding of the biological functions of the candidate genes in the PP-fold pathway. Furthermore, the high-risk clinical samples provide us with a unique opportunity to explore biomarker utility of plasma PYY in MetS, and to uncover mechanisms underlying the notorious weight-gain effects of the ATAPs. The results of this genetic study with a translational research component are anticipated to yield substantial advances in interpretation and validation of the in vivo associations, and reveal their molecular functions in obesity/MetS susceptibility and pathogenesis, thereby providing new insights into the etiology, classification, and design of novel therapeutic interventions.