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: 8662245
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662245
• 关键词: Adenylate Cyclase; Affinity; Agonist; 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; deep sequencing; 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; rare variant; receptor; receptor expression; response; responsible research conduct; risk variant; 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。我的研究结合了实验和统计方法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。获得博士学位后。我在匹兹堡大学获得遗传流行病学博士学位，并于 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 UCSD 获得了富有成效的奖学金培训经历，发表了 8 篇出版物（还有 5 篇正在审查/进展中），获得了两项奖学金研究奖，并两次获得 NKF 青年研究员奖（两次均获得第一）。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背后的生物学机制。此外，我的目标是将我的遗传流行病学研究扩展到基于临床的高风险患者群体，从而获得转化研究方面的专业知识。凭借我通过 K01 职业发展补助金获得的技能，将会产生新的见解，从而改善临床实践中肥胖和相关疾病风险的管理。我的长期（10 年及更长）职业目标是成为一名独立的学术教员，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发现，以改善高危患者群体的临床护理。这个 K01 奖项将使我沉浸在一个丰富的环境中，在这个环境中，多学科研究人员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接受过良好的培训，并且已经在加州大学圣地亚哥分校的医学和精神病学系熟练地工作。然而，由于这只是我的第四个博士后年，为了作为一名独立的首席研究员具有竞争力，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Ming T. Tsuang博士和Daniel T. O'Connor博士的直接监督下，我们为我在K01支持的五年（2011-2016）期间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，以及 (2) 基因组技术和分子生物学- 这涵盖基因组技术、生物信息学和分子生物学中使用的技术。项目摘要。标题：PP 折叠多肽受体轴对代谢综合征风险的遗传学研究。全球肥胖率不断上升，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，促进糖尿病和心血管疾病的流行。 MetS 中定义的每个临床特征都很大程度上受到遗传决定的影响，但导致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 PP 折叠多肽，可激活 G 蛋白偶联受体 NPY1R 和 NPY2R，从而调节饱腹感、新陈代谢和血管收缩。血浆 NPY 和 PYY 水平与饮食和代谢紊乱相关，但由于 PP 折叠肽的混合神经元和激素功能及其结合两种受体的能力，很难确定关联背后的精确机制。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 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：通过以下方式确定风险等位基因的功能作用： (3) 探索性转化研究：表征非典型抗精神病药物 (ATAP) 治疗后血浆 PYY 在肥胖和 MetS 风险中的作用，并评估 ATAP 对 PYY 通路信号转导的影响体外。这一跨学科提案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 折叠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 ATAP 臭名昭著的体重增加效应背后的机制。这项具有转化研究成分的遗传学研究的结果预计将在体内关联的解释和验证方面取得实质性进展，并揭示它们在肥胖/MetS易感性和发病机制中的分子功能，从而为病因学、分类、和新型治疗干预措施的设计。

项目成果

Modifying resilience mechanisms in at-risk individuals: a controlled study of mindfulness training in Marines preparing for deployment.

• DOI: 10.1176/appi.ajp.2014.13040502
• 发表时间: 2014-08
• 期刊: The American journal of psychiatry
• 作者: Johnson DC;Thom NJ;Stanley EA;Haase L;Simmons AN;Shih PA;Thompson WK;Potterat EG;Minor TR;Paulus MP
• 通讯作者: Paulus MP