Cntnap2 in diet-induced obesity

描述(申请人提供)：在美国和整个发达国家，肥胖是一个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。虽然最近的疫情主要是由环境因素推动的，但有强有力的证据表明，未知的遗传因素对个人体重增加的倾向有显著影响。为了更好地了解这些遗传因素，我们研究了C57BL/6J和A/J小鼠，它们对卡路里丰富的环境做出了不同的反应。尽管在正常情况下，C57BL/6J小鼠的生理机能相似，但它们会变得肥胖，并出现许多代谢综合征的症状，而A/J小鼠则保持相对较瘦的状态。我已经将导致肥胖菌株差异的一个遗传因素定位到6号染色体上只包含一个基因cntnap2的区域。C57BL/6J和A/J的CNTNAP2有2个氨基酸残基不同，这些变异可能导致这两个毒株编码蛋白的功能差异，从而导致肥胖易感性的差异。我们建议使用结合遗传学、生理学和生化的方法来研究cntnap2和一个功能相关基因在肥胖中的作用。将建立一个基因敲除的小鼠模型，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并发症。提出的实验将极大地帮助我们科学地理解肥胖和糖尿病的分子机制。布克纳博士之前的培训重点是复杂疾病的遗传学。这项提议旨在通过在生理学和线粒体生物化学领域开展更多职业发展活动来补充这一培训。这将通过额外的课程作业、与拟议研究相关领域的专家团队的实践经验以及来自纳多博士和查尔斯·霍佩尔博士的重要指导来实现，他们在各自的遗传学(纳多)和线粒体生物化学(霍佩尔)领域是国际公认的专家。除了具体的新陈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。职业发展计划的另一个重要组成部分是出席和介绍国家和国际研究会议。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。纳多和霍佩尔博士的指导，以及与一群有成就的研究人员的合作，将提供一个特殊的环境，让他们学习新的技能和知识，这将有助于布克纳博士在学术机构成为一名高效的独立研究员。 与公共健康相关：考虑到肥胖对健康的巨大影响，识别复杂遗传性肥胖小鼠模型背后的基因将是非常有益的。这可能导致在人类中发现类似的因素，使个人容易显著增加体重，并允许这些人相应地改变他们的生活方式。此外，识别对体重增加有显著影响的基因或途径的变异可能为安全有效的药物干预提供潜在的治疗靶点。

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.