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

PP折叠多肽受体轴对代谢综合征风险的遗传学研究

• 批准号: 8288876
• 负责人: Pei-an (Betty) Shih
• 金额: $ 13.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288876
• 关键词: Adenylate Cyclase; Affinity; Agonist; Alleles; Amino Acid Substitution; Animal Model; Award; Binding; Bioinformatics; Biological; Biological Markers; Biological Process; Body mass index; Brain region; California; Candidate Disease Gene; Cardiovascular Diseases; Cells; Cellular biology; Classification; Cleaved cell; Clinic; Clinical; Clinical Trials; Code; Complex; Coupled; Cyclic AMP; Desire for food; Development; Development Plans; Diabetes Mellitus; Dimensions; Disease; Doctor of Philosophy; Down-Regulation; Eating Disorders; Educational process of instructing; Environment; Epidemic; Epidemiology; Etiology; Faculty; Fellowship; Foundations; Frequencies; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Techniques; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Heritability; Hormonal; Human; Hypertension; In Vitro; Inherited; Interdisciplinary Study; Kidney; Knowledge; Lead; Medicine; Mentored Research Scientist Development Award; Mentors; Metabolic Diseases; Metabolic syndrome; Metabolism; MicroRNAs; Molecular; Molecular Biology; Molecular Biology Techniques; Molecular Genetics; Neurons; Neuropeptides; Obesity; Obesity associated disease; Pathogenesis; Pathway interactions; Patients; Peptide Receptor; Peptide YY; Peptides; Peripheral; Plasma; Post-Transcriptional Regulation; Predisposition; Prevalence; Principal Investigator; Psychiatry; Publications; Receptor Signaling; Regulation; Reporter; Research; Research Design; Research Methodology; Research Personnel; Research Project Grants; Resistance; Risk; Risk Factors; Role; Sampling; Satiation; Signal Transduction; Signal Transduction Pathway; Supervision; System; TATA Box; Techniques; Technology; Time; Training; Transcriptional Regulation; Translating; Translational Research; Universities; Untranslated Regions; Validation; Variant; Weight Gain; Work; abstracting; atypical antipsychotic; base; career; career development; clinical care; clinical practice; density; design; disorder risk; epidemiology study; experience; gene interaction; genetic association; genetic epidemiology; genetic variant; genome wide association study; high risk; improved; in vivo; insight; interdisciplinary approach; mRNA Stability; member; multidisciplinary; novel therapeutic intervention; patient population; polypeptide; promoter; receptor; receptor expression; response; responsible research conduct; skills; statistics; trait; transcription factor; translational study; vasoconstriction

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.

描述（由申请人提供）：候选人。我的研究将实验和统计方法汇集到人类复合物和多基因疾病的遗传基础，特别强调代谢综合征。获得我的博士学位后匹兹堡大学的遗传流行病学博士学位，我于2007年加入加利福尼亚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有一项富有成效的奖学金培训经验，产生了8个出版物（在评论/进度方面还有5个出版物），获得了两个研究金研究奖，并在两次分别获得了NKF的年轻研究者奖（两次将首次放置）。我的短期（5年）目标是获得分子生物学技能，以发现与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诊所的患者人群中，以获取转化研究的专业知识。通过我将通过这笔K01职业发展赠款获得的技能，将产生新的见解，以改善临床实践中肥胖和相关疾病风险的管理。我的长期（十年及以后）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，我预计我的扩展知识和技能将直接转化为遗传和基因组发现，以改善高危患者人群的临床护理。这个K01奖将使我能够沉浸在一个丰富的环境中，其中一个多学科的调查人员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。我已经在遗传技术（小规模的基因序列和基因分型），统计和遗传流行病学方面受过良好的训练，并且已经在UCSD的医学和精神病学系在熟练的水平上发挥作用。但是，由于这只是我第四个博士后年，因此我必须发展一些专业知识，才能成为独立的主要研究者 - 分子/细胞生物学和转化研究方法。 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)基因组技术与分子生物学 - 涵盖了基因组技术，生物信息学和分子生物学中使用的技术。项目摘要。标题：PP折叠多肽受体轴对代谢综合征风险的遗传研究。肥胖率在全球范围内上升，导致代谢综合征（METS）的患病率增加。大都会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兴流行。 MetS内定义的每个临床特征都受到遗传性确定的很大影响，但是造成这些特征的遗传变异的身份及其分子机制仍然难以捉摸。肽YY（PYY）和神经肽（NPY）是激活G蛋白偶联受体NPY1R和NPY2R的PP折叠多肽，可调节饱腹感，代谢和血管收缩。血浆NPY和PYY水平与饮食和代谢性疾病相关，但由于PP折叠肽的神经元和激素功能互混合的神经元和激素功能以及它们结合两种受体的能力，因此难以识别基础关联的确切机制。在这里，我们将新兴的基因组和分子生物学技术与3层关联研究设计融为一体，以应对PP折叠多肽受体途径在肥胖症和Mets风险中的作用。我们有三个具体的目的：（1）体内遗传关联：评估稀有（异常）与常见遗传变异在PP折叠肽途径中的作用，（2）分子生物学：确定通过体外方法来确定风险等位基因的功能作用，（3）探索性转化研究：（3）探索性的质量和质量（质量质量）的作用（表征）质量（质量质量）。治疗并评估ATAP对PYY途径信号转导体外的影响。该跨学科的建议将分子遗传学和遗传流行病学融合了分子生物学研究，以提高我们对PP途径中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，可以探索MetS中血浆PYY的生物标志物实用性，并发现ATAPS臭名昭著的体重增加作用的机制。预计这项具有转化研究成分的遗传研究结果将在解释和验证体内关联方面取得重大进展，并揭示其在肥胖/MetS易感性和发病机理中的分子功能，从而为新颖的治疗干预措施提供了新的见解，从而提供了新的见解。