Targeting a Novel Regulator of Brain Aging and Alzheimer's Disease

针对大脑衰老和阿尔茨海默病的新型调节剂

• 批准号: 8921933
• 负责人: Li-Huei Tsai
• 金额: $ 87.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921933
• 关键词: Affect; Aging; Alzheimer' s Disease; Applications Grants; Area; Biological Preservation; Brain; Brain region; Cell Death; Complement; Development; Elderly; Gene Expression; Gene Expression Profile; Genes; Genome; Goals; HDAC1 gene; Health; Hereditary Disease; Hippocampus (Brain); Human; Impaired cognition; Individual; Inflammation; Informatics; Knockout Mice; Maps; Microglia; Nerve Degeneration; Neurons; Oxidative Stress; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Preclinical Drug Evaluation; Principal Investigator; Regulation; Regulator Genes; Religion and Spirituality; Risk Factors; Role; Sampling; Signal Transduction; Staging; Stress; Synapses; System; Technology; Therapeutic Agents; Validation; age related; aging brain; base; cell type; cognitive function; genetic approach; insight; interdisciplinary approach; loss of function; mild cognitive impairment; neuroinflammation; neurotoxic; new therapeutic target; normal aging; novel; novel therapeutic intervention; novel therapeutics; pathological aging; response; small molecule; stressor; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): This R01 grant proposal is in response to RFA-AG-13-013 "Interdisciplinary Approach to Identification and Validation of Novel Therapeutic Targets for Alzheimer's Disease". The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease (AD). Despite this central role in disease, the molecular underpinnings of brain aging and the transition from normal to pathological aging are poorly understood. The overall goal of this proposal is to gain new insights into healthy brain aging and the transition to AD by exploring the role of a newly identified neuroprotective regulatory network. We have recently discovered that the master developmental regulator REST/NRSF is induced in the aging human brain and together with HDAC1 coordinates the expression of a gene network that may protect aging neurons from neurotoxic stress, synapse loss and overexcitation. This pathway regulates the expression of a large number of genes in the aging brain that are involved in cell death, inflammation, oxidative stress and AD pathology. Induction of REST correlates with preservation of cognitive function during aging, whereas loss of function is associated with onset of cognitive decline in patients with mild cognitive impairment. REST function is almost completely abrogated in affected brain regions in AD. Our preliminary results implicate this pathway in the regulation of two major cell types in the aging brain, neurons and microglia. The studies in this proposal seek to elucidate the regulatory role of the REST network in protecting aging neurons from age-related stressors, reducing neuroinflammation and preserving cognitive function using REST and HDAC1 conditional knockout mice. New high-sensitivity transcriptome sequencing technology together with informatics analysis using tools from the Personal Genome Project will be used to define the REST-regulated gene network. By applying this systems genetics approach to well-characterized human brain samples from the Religious Orders study, we will attempt to define REST-regulated gene networks predictive of successful aging, early cognitive decline and AD. A central question is how this gene network systematically fails in individuals who develop AD, and whether this decline can be reversed. The discovery that REST can be activated through stimulation of Wnt signaling using known drugs, as well as newly identified small molecule agents, raises the exciting possibility that the aging brain could be protected by a novel therapeutic approach based on activation of the REST network. These studies will bring together three principal investigators and many collaborators with diverse but complementary areas of expertise in a multidisciplinary approach to understand the transition from normal brain aging to AD.

描述(由申请人提供)：这份R01拨款提案是对RFA-AG-13-013“确定和验证阿尔茨海默病新治疗靶点的跨学科方法”的回应。大脑老化是老年人认知能力下降的原因之一，也是阿尔茨海默病(AD)的主要危险因素。尽管在疾病中起着核心作用，但人们对大脑老化的分子基础以及从正常衰老到病理性衰老的转变知之甚少。这项提案的总体目标是通过探索新发现的神经保护调节网络的作用，对健康的大脑衰老和向AD的过渡获得新的见解。我们最近发现，主要的发育调节因子REST/NRSF在老化的人脑中被诱导，并与HDAC1一起协调一个基因网络的表达，该基因网络可能保护老化的神经元免受神经毒性应激、突触丢失和过度兴奋的影响。这一途径调节衰老大脑中大量基因的表达，这些基因涉及细胞死亡、炎症、氧化应激和AD病理。在轻度认知障碍的患者中，静息的诱导与认知功能的保持有关，而功能的丧失与认知功能下降的开始有关。阿尔茨海默病患者受影响脑区的静息功能几乎完全丧失。我们的初步结果表明，这一途径参与了衰老大脑中两种主要细胞类型的调节，即神经元和小胶质细胞。这项建议中的研究试图阐明REST网络在利用REST和HDAC1条件基因敲除小鼠保护老化神经元免受年龄相关应激源的影响、减少神经炎症和保护认知功能方面的调节作用。新的高灵敏度转录组测序技术将与使用个人基因组计划工具的信息学分析一起用于定义REST调控的基因网络。通过将这种系统遗传学方法应用于宗教教团研究中具有良好特征的人脑样本，我们将试图定义预测成功衰老、早期认知衰退和阿尔茨海默病的休息调节基因网络。一个核心问题是，这种基因网络是如何系统性地在阿尔茨海默病患者身上失灵的，这种下降是否可以逆转。REST可以通过使用已知药物和新发现的小分子药物刺激Wnt信号来激活这一发现，这一发现提出了一种令人兴奋的可能性，即基于激活REST网络的新治疗方法可以保护老化的大脑。这些研究将汇集三名主要研究人员和许多具有不同但互补的专业知识领域的合作者，以多学科的方法了解从正常脑老化到AD的转变。