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

描述（由申请人提供）：候选人。我的研究将实验和统计方法结合起来，研究人类复杂和多基因疾病的遗传基础，特别强调代谢综合征。在匹兹堡大学获得遗传流行病学博士学位后，我于2007年加入加州大学圣地亚哥分校高血压研究实验室，担任国家肾脏基金会（NKF）研究员。我在加州大学圣地亚哥分校有一段富有成效的奖学金培训经历，发表了8篇论文（还有5篇正在审查/进展中），获得了两次奖学金研究奖，并两次获得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，以揭示性状相关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危临床患者群体，获得转化研究方面的专业知识。我将通过K01职业发展基金获得的技能，将产生新的见解，应该在临床实践中改善肥胖和相关疾病风险的管理。我的长期（10年及以上）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，我希望我扩大的知识和技能将直接转化为基因和基因组的发现，以改善高危患者群体的临床护理。这个K01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我的职业目标所需的统计和分子生物学技能。职业发展计划。我已经在基因技术（小规模基因测序和基因分型）、统计学和遗传流行病学方面接受了良好的培训，并且已经在加州大学圣地亚哥分校的医学和精神病学部门发挥了熟练的作用。然而，由于这只是我博士后的第四年，为了成为一名有竞争力的独立首席研究员，我必须发展一些专业知识——分子/细胞生物学和转化研究方法。在我的导师Dr. Ming T. Tsuang和Dr. Daniel T. O'Connor的直接指导下，我在K01支持的五年（2011-2016）里为我的职业发展设计了一个全面的培训计划：(1)遗传流行病学和转化研究设计-涵盖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知识，以及负责任的研究行为；(2)基因组技术和分子生物学-涵盖基因组技术，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研究。世界范围内的肥胖率正在上升，导致代谢综合征（MetS）的患病率增加。MetS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新流行。在MetS中定义的每一个临床特征都受到遗传决定的影响，然而遗传变异对这些特征及其分子机制的影响仍然难以捉摸。肽YY （PYY）和神经肽（NPY）是PP-fold多肽，可激活g蛋白偶联受体NPY1R和NPY2R，调节饱腹感、代谢和血管收缩。血浆NPY和PYY水平与饮食和代谢紊乱有关，但由于pp折叠肽具有混合的神经元和激素功能以及它们结合两种受体的能力，因此很难确定这种关联的确切机制。在这里，我们将新兴的基因组和分子生物学技术与三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：评估罕见（不寻常）与常见遗传变异在pp折叠肽途径中的作用；(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：表征血浆PYY在非典型抗精神病药物（ATAP）治疗后肥胖和MetS风险中的作用，并评估ATAP对PYY途径信号转导的影响。这个跨学科的建议将分子遗传学和遗传流行病学与分子生物学研究联系起来，以提高我们对PP-fold途径中候选基因的生物学功能的理解。此外，高风险临床样本为我们提供了一个独特的机会来探索血浆PYY在MetS中的生物标志物效用，并揭示ATAPs臭名昭著的体重增加效应的机制。这项具有翻译研究成分的遗传研究结果有望在体内关联的解释和验证方面取得实质性进展，并揭示其在肥胖/MetS易感性和发病机制中的分子功能，从而为病因、分类和新型治疗干预的设计提供新的见解。

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.