Cntnap2 in diet-induced obesity

Cntnap2 在饮食引起的肥胖中的作用

• 批准号: 8103262
• 负责人: DAVID A BUCHNER
• 金额: $ 14.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103262
• 关键词: A/J Mouse; Affect; Alleles; Amino Acids; Axon; Axonal Transport; Basal metabolic rate; Biochemistry; Blood Pressure; Body Composition; Body Weight; Body mass index; Cardiovascular Diseases; Chromosomes, Human, Pair 6; Clinical; Collaborations; Comorbidity; Complement; Complex; Congenic Strain; Consomic Strain; Defect; Development; Development Plans; Diabetes Mellitus; Diabetic Neuropathies; Diet; Disease; Eating; Environment; Environmental Risk Factor; Epidemic; Equilibrium; Fatty acid glycerol esters; Genes; Genetic; Genetic Polymorphism; Genotype; Glucose; Health; Homologous Gene; Human; Hyperglycemia; Individual; Institution; Insulin; International; Intervention; Journals; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Leptin deficiency; Life Style; Link; Lipids; Liver; Longevity; Malignant Neoplasms; Maps; Measurement; Measures; Medicine; Mentors; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Morphology; Mus; Nerve Fibers; Neural Conduction; Neurons; Neuropathy; Obesity; Overweight; Pathway interactions; Pharmacologic Substance; Phenotype; Physical activity; Physiology; Population; Potassium; Predisposition; Prevalence; Property; Proteins; Quantitative Trait Loci; Ranvier' s Nodes; Research; Research Personnel; Resistance; Role; Series; Severities; Structure; Sucrose; Symptoms; Testing; Thermogenesis; Tissues; Training; Training Activity; Training Programs; Triglycerides; Variant; Weight Gain; aged; base; burden of illness; career development; clinically significant; cohort; contactin; density; diabetes risk; energy balance; experience; feeding; gene discovery; gene environment interaction; improved; mitochondrial dysfunction; mouse model; obesity treatment; post-doctoral training; protein function; public health relevance; research study; skills; symposium; therapeutic target; trait; voltage

DESCRIPTION (provided by applicant): Obesity is an increasingly common health problem in the U.S. and throughout the developed world. Approximately two-thirds of the U.S population is currently obese or overweight. While the recent epidemic is being driven primarily by environmental factors, there is strong evidence for unknown genetic factors that significantly contribute to an individual's propensity for weight gain. To better understand these genetic factors, we have studied C57BL/6J and A/J mice which respond differently to a calorie-rich environment. Despite similar physiology under normal conditions, C57BL/6J mice become obese and develop many of the symptoms of metabolic syndrome while A/J mice remain relatively lean. I have mapped a genetic factor that contributes to this strain difference in adiposity to a region on chromosome 6 that contains only a single gene, Cntnap2. There are 2 amino acid residues in CNTNAP2 that differ between C57BL/6J and A/J. These variants may lead to functional differences in the encoded protein in these two strains, thereby contributing to the difference in obesity susceptibility. We propose to study the role of Cntnap2 and a functionally related gene in obesity using approaches that integrate genetics, physiology, and biochemistry. A knockout mouse model will be generated to study the role of Cntnap2 in adiposity and energy balance as well as a number of clinically important comorbidities of obesity. The experiments proposed will greatly contribute to our scientific understanding of the molecular mechanisms underlying obesity and diabetes. Dr. Buchner's prior training has focused on the genetics of complex disease. This proposal aims to complement this training, with additional career development activities in the fields of physiology and mitochondrial biochemistry. This will be attained through additional coursework, hands-on experience with a team of experts in fields relevant to the proposed research, and significant mentoring from Dr. Nadeau and Dr. Charles Hoppel who are internationally recognized experts in their fields of genetics (Nadeau) and mitochondrial biochemistry (Hoppel). In addition to specific metabolism-related training activities, CWRU and the Department of Genetics will provide a rich mentoring environment for career development. Available activities include weekly scientific seminars, journal clubs, postdoctoral training programs, and many others. Another important component of the career development plan will be attending and presenting at national and international research conferences. Conferences will include an annual Keystone Symposium on obesity and diabetes and an annual Mitochondrial Medicine Conference. The mentoring by Drs. Nadeau and Hoppel, and collaborations with a team of accomplished investigators, will provide an exceptional environment to learn new skills and knowledge that will assist Dr. Buchner as he seeks to become a highly productive independent investigator at an academic institution. PUBLIC HEALTH RELEVANCE: Given the tremendous health impact of obesity, it would be of great benefit to identify the genes that underlie a mouse model of complex genetic obesity. This may lead to the identification of similar factors in humans that predispose individuals to significant weight gain and allow these individuals to modify their lifestyle accordingly. Additionally, identifying variation in genes or pathways with significant effects on weight gain may suggest potential therapeutic targets for safe and effective pharmaceutical intervention.

描述（由申请人提供）：在美国和整个发达国家，肥胖是一个越来越普遍的健康问题。目前大约三分之二的美国人肥胖或超重。虽然最近的流行病主要是由环境因素驱动的，但有强有力的证据表明，未知的遗传因素在很大程度上促成了个人体重增加的倾向。为了更好地了解这些遗传因素，我们研究了C57BL/6J和A/J小鼠，它们对富含卡路里的环境有不同的反应。尽管正常情况下的生理机能相似，但C57BL/6J小鼠变得肥胖，并出现许多代谢综合征的症状，而A/J小鼠保持相对苗条。我已经在6号染色体上的一个区域找到了导致这种肥胖差异的遗传因素，这个区域只包含一个基因Cntnap2。CNTNAP2中有2个氨基酸残基在C57BL/6J和A/J之间存在差异。这些变异可能导致这两种菌株中编码蛋白的功能差异，从而导致肥胖易感性的差异。我们建议使用整合遗传学、生理学和生物化学的方法来研究Cntnap2和一个功能相关基因在肥胖中的作用。我们将建立敲除小鼠模型，研究Cntnap2在肥胖和能量平衡中的作用，以及一些临床上重要的肥胖合并症。提出的实验将极大地有助于我们对肥胖和糖尿病的分子机制的科学理解。Buchner博士之前的培训重点是复杂疾病的遗传学。这项建议旨在补充这一培训，在生理学和线粒体生物化学领域开展额外的职业发展活动。这将通过额外的课程学习，与相关领域的专家团队的实践经验，以及Nadeau博士和Charles Hoppel博士的重要指导来实现，他们是国际公认的遗传学（Nadeau）和线粒体生物化学（Hoppel）领域的专家。除了特定的代谢相关培训活动外，CWRU和遗传学系将为职业发展提供丰富的指导环境。可用的活动包括每周的科学研讨会、期刊俱乐部、博士后培训计划等等。职业发展计划的另一个重要组成部分将是出席国家和国际研究会议并发表演讲。会议将包括关于肥胖和糖尿病的年度Keystone研讨会和年度线粒体医学会议。博士的指导。Nadeau和Hoppel，以及与有成就的调查员团队的合作，将提供一个特殊的环境来学习新的技能和知识，这将有助于Buchner博士成为一个学术机构的高效独立调查员。