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）：此 R01 拨款提案是对 RFA-AG-13-013“识别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一个原因，也是阿尔茨海默病（AD）的主要危险因素。尽管在疾病中发挥着重要作用，但大脑衰老的分子基础以及从正常衰老到病理性衰老的转变仍知之甚少。该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，获得对健康大脑衰老和向 AD 过渡的新见解。我们最近发现，主要的发育调节因子 REST/NRSF 在衰老的人脑中被诱导，并与 HDAC1 一起协调基因网络的表达，该基因网络可以保护衰老的神经元免受神经毒性应激、突触损失和过度兴奋的影响。该通路调节衰老大脑中大量与细胞死亡、炎症、氧化应激和AD病理有关的基因的表达。休息的诱导与衰老过程中认知功能的保存相关，而功能的丧失则与轻度认知障碍患者认知能力下降相关。 AD 受影响的大脑区域的休息功能几乎完全消失。我们的初步结果表明该途径参与了衰老大脑中两种主要细胞类型（神经元和小胶质细胞）的调节。本提案中的研究旨在利用 REST 和 HDAC1 条件敲除小鼠阐明 REST 网络在保护衰老神经元免受年龄相关压力源影响、减少神经炎症和保留认知功能方面的调节作用。新的高灵敏度转录组测序技术以及使用个人基因组计划工具的信息学分析将用于定义 REST 调节的基因网络。通过将这种系统遗传学方法应用于宗教秩序研究中明确表征的人类大脑样本，我们将尝试定义 REST 调节的基因网络，以预测成功衰老、早期认知衰退和 AD。一个核心问题是这个基因网络如何在患有AD的个体中系统性地失效，以及这种下降是否可以逆转。 REST 可以通过使用已知药物以及新发现的小分子药物刺激 Wnt 信号传导来激活，这一发现提出了一种令人兴奋的可能性，即基于 REST 网络激活的新型治疗方法可以保护衰老的大脑。这些研究将汇集三位主要研究人员和许多具有不同但互补的专业领域的合作者，采用多学科方法来了解从正常大脑衰老到 AD 的转变。