Cntnap2 in diet-induced obesity

描述（由申请人提供）：肥胖是美国和整个发达国家日益普遍的健康问题。目前，大约三分之二的美国人口肥胖或超重。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，未知的遗传因素对个体的体重增加倾向有显著影响。为了更好地了解这些遗传因素，我们研究了C57 BL/6 J和A/J小鼠，它们对高热量环境的反应不同。尽管在正常条件下具有相似的生理机能，但C57 BL/6 J小鼠变得肥胖并出现代谢综合征的许多症状，而A/J小鼠保持相对较瘦。我绘制了一个遗传因子，它导致了这种肥胖症的菌株差异，位于6号染色体上的一个区域，该区域只包含一个基因，Cntnap 2。CNTNAP 2中有2个氨基酸残基在C57 BL/6 J和A/J之间不同。这些变体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Cntnap 2和功能相关基因在肥胖中的作用。将产生敲除小鼠模型以研究Cntnap 2在肥胖和能量平衡中的作用以及肥胖的许多临床重要的合并症。提出的实验将大大有助于我们对肥胖和糖尿病潜在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。该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，与拟议研究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，他们是遗传学（Nadeau）和线粒体生物化学（Hoppel）领域的国际公认专家。除了特定的代谢相关的培训活动，CWRU和遗传学系将提供职业发展的丰富的指导环境。可用的活动包括每周科学研讨会，期刊俱乐部，博士后培训计划，以及许多其他。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。会议将包括一年一度的肥胖和糖尿病的基石研讨会和年度线粒体医学会议。Nadeau和Hoppel博士的指导，以及与一个有成就的研究人员团队的合作，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研究者。

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.