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

基本信息

批准号：
8874966
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874966
关键词：
Adenovirus Vector Advisory Committees Affect Alzheimer&apos s Disease Alzheimer&apos 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

项目摘要

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（由申请人提供）：该提案描述了一个为期5年的培训项目，该项目将使我能够实现成为糖尿病研究中独立研究者的目标。培训和职业发展计划包括一个研究项目，对公共卫生，实验室技术的培训以及教学科学和职业发展研讨会和课程具有潜在影响。胰岛素信号和糖尿病领域的领导者C. Ronald Kahn博士将担任我的导师。他已经培训了150多名博士后研究员，其中许多人现在是部门负责人。此外，咨询委员会将为我提供科学和职业建议。该研究将在乔斯林糖尿病中心进行；哈佛大学附属机构，使我获得了哈佛社区必须提供的所有资源。糖尿病患者的认知能力下降和阿尔茨海默氏病的风险增加。连接这些疾病的机制尚不清楚。小鼠的最新数据表明，糖尿病小鼠大脑中胆固醇合成速率降低。鉴于胆固醇转运蛋白（APOE）的变体最大的风险因素最大的危险因素尤其重要。我的初步数据表明，通过敲除脑中固醇感应蛋白SCAP的一份副本来减少胆固醇的合成，从而产生小鼠，其脑胆固醇合成率受损，突触传播中的损伤和认知障碍。该项目的总体目标是了解胰岛素如何调节SREBP-2（胆固醇合成的更具体的调节剂，而不是SCAP）。在AIM 1中，我将定义胰岛素用来刺激大脑中胰岛素信号传导的分子途径。 AIM 2将确定从小鼠中删除SREBP-2的生化后果。 AIM 3将描绘通过将SREBP-2从神经元或神经胶质中敲出的脑功能变化。此外，这些敲除小鼠将成为糖尿病患者或与阿尔茨海默氏病模型交叉，以确定降低胆固醇的背景如何加剧这些疾病。