Insulin and SREBP-2 in brain cholesterol regulation

胰岛素和 SREBP-2 在脑胆固醇调节中的作用

• 批准号: 8704405
• 负责人: Heather Ferris
• 金额: $ 15.03万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704405
• 关键词: Adenovirus Vector; Advisory Committees; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Apolipoprotein E; Behavioral; Binding; Biochemical; Biogenesis; Brain; Breeding; Cell Line; Cell Nucleus; Cerebrum; Chemicals; Cholesterol; Cholesterol Homeostasis; Cleaved cell; Co-Immunoprecipitations; Cognition; Communities; Complex; Data; Dementia; Development; Development Plans; Diabetes Mellitus; Diabetic mouse; Disease; Endoplasmic Reticulum; Fatty Acids; Figs - dietary; Gene Expression; General Population; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; Golgi Apparatus; Head; Hyperglycemia; Impaired cognition; Impairment; In Situ; In Vitro; Institution; Insulin; Insulin Receptor; Insulin Signaling Pathway; Knock-out; Knockout Mice; Laboratories; Late Onset Alzheimer Disease; Link; Lipids; Mediating; Mentors; Metabolic Control; Modeling; Molecular; Molecular Chaperones; Mus; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Organ; Pathway interactions; Patients; Postdoctoral Fellow; Process; Production; Public Health Education; Regulation; Relative (related person); Research; Research Personnel; Research Project Grants; Resources; Response Elements; Risk; Risk Factors; Role; SCAP protein; SRE-1 binding protein; SRE-2 binding protein; Signal Pathway; Signaling Molecule; Steroids; Sterols; Streptozocin Diabetes; Synapses; Synaptic Transmission; Techniques; Time; Tissues; Training; Translating; Triglycerides; Variant; Vesicle; Western Blotting; Wild Type Mouse; career; career development; cell type; cholesterol transporters; cognitive function; diabetic; diabetic patient; disease phenotype; in vivo; inhibitor/antagonist; insulin secretion; insulin signaling; lipid metabolism; mouse model; nestin protein; sensor; small hairpin RNA; training project; type I and type II diabetes

DESCRIPTION (provided by applicant): This proposal describes a 5 year training project that will allow me to achieve my goal of becoming an independent investigator in diabetes research. The training and career development plan includes a research project with potential implications for public health, training in laboratory techniques, and didactic scientific and career development seminars and courses. Dr. C. Ronald Kahn, a leader in the field of insulin signaling and diabetes, will serve as my mentor. He has trained over 150 postdoctoral fellows, many of whom are now department heads. In addition, an advisory committee will provide me with scientific and career advice. The research will take place at the Joslin Diabetes Center; a Harvard affiliated institution, providing me access to all of the resources the Harvard Community has to offer. There is an increased risk of cognitive decline and Alzheimer's disease in patients with diabetes. The mechanism connecting these diseases is unclear. Recent data in mice demonstrate a decrease in the rate of cholesterol synthesis in the brains of diabetic mice. This is particularly significant given that the greatest risk factor for late onset Alzheimer's disease s a variant in a cholesterol transporter (ApoE). My preliminary data demonstrate that decreasing cholesterol synthesis by knocking out one copy of the sterol sensing protein SCAP in the brain produces mice with an impaired rate of cerebral cholesterol synthesis, impairment in synaptic transmission, and cognitive impairment. The overall goal of the project is to understand how insulin regulates SREBP-2, a more specific regulator of cholesterol synthesis than SCAP. In Aim 1 I will define the molecular pathway used by insulin to stimulate insulin signaling in the brain. Aim 2 will determine the biochemical consequences of deleting SREBP-2 from neurons and glia in mice. Aim 3 will delineate the changes in brain function produced by knocking SREBP-2 out from neurons or glia. In addition, these knockout mice will be made diabetic or crossed with a model of Alzheimer's disease to determine how a background of reduced cholesterol exacerbates these diseases.

描述(由申请者提供)：这份建议书描述了一个为期5年的培训项目，它将使我实现成为糖尿病研究的独立研究员的目标。培训和职业发展计划包括一个对公共卫生有潜在影响的研究项目、实验室技术培训以及教学科学和职业发展研讨会和课程。胰岛素信号和糖尿病领域的领军人物C.Ronald Kahn博士将担任我的导师。他培养了150多名博士后研究员，其中许多人现在是系主任。此外，一个咨询委员会将为我提供科学和职业建议。这项研究将在乔斯林糖尿病中心进行，这是哈佛大学的一个附属机构，为我提供了哈佛社区提供的所有资源。糖尿病患者患认知功能减退和阿尔茨海默病的风险增加。这些疾病之间的联系机制尚不清楚。最近在小鼠身上的数据表明，糖尿病小鼠大脑中胆固醇合成的速度有所下降。这一点尤其重要，因为迟发性阿尔茨海默病的最大风险因素是S，一种胆固醇转运蛋白(ApoE)的变异。我的初步数据表明，通过敲除大脑中的一种类固醇感应蛋白SCAP来减少胆固醇合成，会导致小鼠大脑胆固醇合成受损，突触传递障碍，以及认知障碍。该项目的总体目标是了解胰岛素如何调节SREBP-2，SREBP-2是一种比SCAP更特异的胆固醇合成调节因子。在目标1中，我将定义胰岛素用来刺激大脑中的胰岛素信号的分子途径。目的2将确定从小鼠神经元和神经胶质细胞中删除SREBP-2的生化后果。目标3将描述通过将SREBP-2从神经元或神经胶质细胞中剔除而产生的脑功能变化。此外，这些基因敲除的小鼠将被制成糖尿病或与阿尔茨海默病模型杂交，以确定胆固醇降低的背景如何加剧这些疾病。