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

描述（由申请人提供）：候选人。我的研究汇集了实验和统计方法，以人类复杂和多基因疾病的遗传基础，特别强调代谢综合征。在获得博士学位后，在匹兹堡大学遗传流行病学方面，我于2007年加入了加州大学圣地亚哥分校的高血压研究实验室，担任国家肾脏基金会（NKF）研究员。我在UCSD有一个富有成效的奖学金培训经验，产生了8篇出版物（有5篇在审查/进展中），获得了两个奖学金研究奖，并在两个不同的场合赢得了NKF的青年研究者奖（两次都是第一名）。我的短期（5年）目标是获得分子生物学技能，以揭示与性状相关的遗传变异的生物学机制。此外，我的目标是通过将我的遗传流行病学研究扩展到高风险的临床患者群体来获得转化研究的专业知识。随着技能，我将通过这个K 01职业发展补助金获得，将产生新的见解，应改善肥胖和相关疾病的风险在临床实践中的管理。我的长期（10年及以后）职业目标是成为一名独立的学术教师，与跨学科研究团队合作，设计协作方法来解决复杂的生物医学问题。更具体地说，我预计我扩大的知识和技能将直接转化为遗传和基因组研究结果，以改善高风险患者群体的临床护理。这个K 01奖将让我沉浸在一个丰富的环境中，一个多学科的研究团队将教我实现职业目标所需的统计和分子生物学技能。职业发展计划。我已经在遗传技术（小规模基因测序和基因分型），统计学和遗传流行病学方面受过良好的训练，并且已经在UCSD的医学和精神病学部门工作。然而，由于这只是我博士后的第四年，我必须发展一些专业知识，以便作为一名独立的首席研究员具有竞争力-分子/细胞生物学和转化研究方法。在我的导师Ming T博士的直接指导下，Tsuang和丹尼尔T.奥康纳，一个全面的培训计划已被设计为我的职业发展在拟议的五年K 01的支持（2011年至2016年）：（1）遗传流行病学和转化研究设计-这包括遗传流行病学和统计学、探索性转化研究、人类研究项目的基础以及负责任的研究行为，和（2）基因组技术和分子生物学-这包括基因组技术，生物信息学和分子生物学中使用的技术。项目摘要。标题：PP折叠多肽-受体轴与代谢综合征风险的遗传学研究。肥胖率在全球范围内不断上升，导致代谢综合征（MetS）的患病率增加。代谢综合征是一组相互关联的危险因素，促进了糖尿病和心血管疾病的流行。MetS中定义的每个临床特征都受到遗传决定的影响，但导致这些特征及其分子机制的遗传变异的身份仍然难以捉摸。肽YY（PYY）和神经肽（NPY）是PP折叠多肽，其激活G蛋白偶联受体NPY 1 R和NPY 2 R以调节饱腹感、代谢和血管收缩。血浆NPY和PYY水平与进食和代谢紊乱相关，但由于PP折叠肽的神经元和激素功能混杂以及它们结合两种受体的能力，导致相关性的精确机制难以确定。在这里，我们将新兴的基因组和分子生物学技术与3层关联研究设计相结合，以解决PP折叠多肽受体途径在肥胖和MetS风险中的作用。我们有三个具体目标：（1）体内遗传关联：评估PP折叠肽途径中罕见（不寻常）与常见遗传变异的作用，（2）分子生物学：通过体外方法确定风险等位基因的功能作用，（3）探索性转化研究：描述血浆PYY在非典型抗精神病药（ATAP）治疗后肥胖和MetS风险中的作用，体外研究ATAP对PYY信号转导通路的影响。这个跨学科的建议桥梁分子遗传学和遗传流行病学与分子生物学研究，以提高我们的PP折叠途径中的候选基因的生物学功能的理解。此外，高风险的临床样本为我们提供了一个独特的机会，探索MetS中血浆PYY的生物标志物效用，并揭示ATAP臭名昭著的体重增加效应的潜在机制。这项遗传研究的结果与转化研究的组成部分，预计将产生实质性的进展，在体内协会的解释和验证，并揭示其在肥胖/代谢综合征的易感性和发病机制的分子功能，从而提供新的见解的病因，分类和设计的新的治疗干预措施。

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.