Caloric restriction and Alzheimers ABeta clearance pathway

热量限制和阿尔茨海默病 Aβ 清除途径

基本信息

批准号：
8411069
负责人：
Berislav V Zlokovic
金额：
$ 7.56万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411069
关键词：
Abeta clearance Advanced Glycosylation End Products Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloidosis Arteries Behavior Binding Binding Proteins Biomedical Research Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Caloric Restriction Cerebral Amyloid Angiopathy Cerebrovascular system Cerebrum Cholesterol Cholesterol Homeostasis Chronic Cognition Collaborations Companions Data Diet Endothelium Excision Fasting Gene Transfer Generations Genes Goals Grant Hepatic Homeobox Genes Human Institutes Institution Iowa Kidney LDL-Receptor Related Protein 1 LDL-Receptor Related Protein 2 Lipoprotein Receptor Liver Los Angeles Mediating Mesenchyme Methods Modeling Mus Mutation Neurosciences Neurosciences Research Neurotoxins Pathology Pathway interactions Peptides Pericytes Peripheral Plasma Productivity Proteins Reporting Research Research Personnel Response Elements Scientist Serbia Serum Response Factor Site Smooth Muscle Myocytes Sterols Study of serum Synapses Talents Testing Toxin Training Transgenes Transgenic Mice Transgenic Organisms Universities Visit amyloid peptide base biological research cerebrovascular cognitive function dietary restriction experience feeding improved member mind control molecular pathology myocardin new therapeutic target next generation peptide A prevent public health relevance receptor research facility skills transgenic model of alzheimer disease

项目摘要

This research will be done primarily in Serbia at the Institute for Biological Research University of Belgrade (LMIC site) in collaboration with Selma Kanazir with the companion grant being R37AG023084, 9/15/2004 to 8/31/2014. We propose to extend aim 4 of the companion grant to study the effects of caloric dietary restriction (DR) on brain and systemic clearance of Alzheimer's disease (AD) neurotoxin amyloid ¿-peptide (A¿) and on cognitive functions using a transgenic model of AD-like cerebral ¿-amyloidosis. The proposed research will significantly enhance the neuroscience research capacity at the LMIC site which is a major biomedical research institution in Serbia and the capabilities of both the LMIC collaborator and the next generation of Serbian researchers to study brain disorders. The LMIC site has experience in DR models. DR reduces A¿ pathology and improves behavior in mice with AD-like cerebral pathology, but the molecular and cellular mechanisms of this improvement remain elusive. The major goal of this proposal is to determine the effects of DR on (i) brain and systemic A¿ clearance mediated by the sterol response element binding protein 2 (SREBP2)/low density lipoprotein receptor related protein 1 (LRP1) and (ii) cognitive functions. LRP1-mediated A¿ clearance in the cerebrovascular system, blood and liver is the major mechanism for removal of A¿ toxin. SREBP2, a key gene regulating cholesterol metabolism, is a major transcriptional suppressor of LRP1. DR or 24 h fasting downregulates SREBP2 in the liver and brain and increases LRP1 expression as shown by Kanazir's pilot data. Our central hypothesis is that DR downregulates SREBP2 in brain vasculature and liver which in turn increases LRP1 activity promoting brain and systemic A¿ clearance thereby improving cognitive functions. We will study APPsw/0 mice on normal diet or DR (aim 1) and with forced SREBP2 expression induced by myocardin gene transfer to brain blood vessels (aim 2). APPsw/0 mice have been transferred to Belgrade in Nov 2010 to allow Kanazir to start her own colony. This is the first transgenic colony established at the Belgrade University. Members of the Kanazir group are versed with the proposed methods to be performed at the LMIC site and will continue to be trained by Zlokovic's group in new state-of-the art methods as needed. Prior to the FIRCA proposal, Zlokovic visited Kanazir and members of her team in Belgrade during January and June 2010, and Kanazir spent 4 months in Zlokovic's former lab in Rochester from Aug 4 to Dec 7, 2010. Kanazir provided creative and important scientific input to the research plan of the FIRCA. This proposal will contribute to building much needed research capacity at the University of Belgrade by enabling the LMIC site to expand research in brain disorders, to introduce new technological approaches, and develop existing research facilities. It will enable short exchange visits of junior researchers between Belgrade and Los Angeles and help improve the productivity and build enthusiasm among young Serbian researchers. We expect the proposal will establish a long-standing collaboration between the Zlokovic group and the LMIC site/PI's group.

这项研究将主要在塞尔维亚贝尔格莱德大学生物研究所进行（LMIC 网站）与 Selma Kanazir 合作，配套赠款为 R37AG023084，2004 年 9 月 15 日至 2014 年 8 月 31 日。我们建议扩大配套补助金的目标 4，以研究热量饮食限制的影响。 (DR) 对阿尔茨海默病 (AD) 神经毒素淀粉样蛋白的大脑和全身清除 ¿ -肽 (A¿) 等使用 AD 样大脑转基因模型研究认知功能 ¿ - 淀粉样变性。显着增强 LMIC 基地的神经科学研究能力，这是一个主要的生物医学基地塞尔维亚的研究机构以及中低收入国家合作者和下一代的能力塞尔维亚研究人员研究大脑疾病，具有 DR 模型的经验。病理学并改善患有 AD 样脑病理学小鼠的行为，但分子和细胞这种改进的机制仍然难以捉摸。该提案的主要目标是确定其效果。 (i) 大脑和全身 A 的 DR由甾醇反应元件结合蛋白 2 介导的清除 (SREBP2)/低密度脂蛋白受体相关蛋白 1 (LRP1) 和 (ii) LRP1 介导的认知功能。一个脑血管系统、血液和肝脏中的清除是清除A¿的主要机制毒素。 SREBP2 是调节胆固醇代谢的关键基因，是 DR 或 LRP1 的主要转录抑制因子。 24 小时禁食会下调肝脏和大脑中的 SREBP2，并增加 LRP1 的表达，如下所示 Kanazir 的试验数据我们的中心假设是 DR 下调脑血管系统和肝脏中的 SREBP2。这反过来又增加了 LRP1 活性，促进大脑和全身 A¿间隙从而改善我们将研究正常饮食或 DR（目标 1）以及强制 SREBP2 表达的 APPsw/0 小鼠。由心肌素基因转移至脑血管（目标 2）诱导。贝尔格莱德于 2010 年 11 月允许卡纳齐尔建立自己的殖民地，这是在贝尔格莱德建立的第一个转基因殖民地。贝尔格莱德大学的成员熟悉所提出的方法。在 LMIC 站点，并将根据需要继续接受 Zlokovic 团队关于新的最先进方法的培训。在 FIRCA 提案之前，Zlokovic 一月份拜访了卡纳齐尔及其在贝尔格莱德的团队成员 2010年8月4日至2010年6月，卡纳齐尔于2010年8月4日至12月7日在兹洛科维奇位于罗切斯特的前实验室待了4个月。卡纳齐尔为 FIRCA 的研究计划提供了创造性和重要的科学投入。通过启用 LMIC 站点，为贝尔格莱德大学建设急需的研究能力做出贡献扩大脑部疾病的研究，引入新技术方法，并开发现有的研究设施将使贝尔格莱德和洛杉矶之间的初级研究人员能够进行短期交流。并帮助提高塞尔维亚年轻研究人员的生产力和热情。该提案将在 Zlokovic 小组和 LMIC 站点/PI 小组之间建立长期合作关系。