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: 9321469
• 负责人: Li-Huei Tsai
• 金额: $ 97.84万
• 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/9321469
• 关键词: Affect; Aging; Alzheimer' s Disease; Applications Grants; Area; Biological Preservation; Brain; Brain region; Cell Death; Complement; Development; Disease; Elderly; Gene Expression; Genes; Genome; Goals; HDAC1 gene; Hippocampus (Brain); Human; Impaired cognition; Individual; Inflammation; Informatics; Knockout Mice; Maps; Microglia; Molecular; 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; Stress; Synapses; System; Technology; Therapeutic Agents; Validation; WNT Signaling Pathway; 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; public health relevance; response; small molecule; stressor; tool; transcriptome; 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）：该R01赠款提案是对RFA-AG-13-013的回应，“识别和验证阿尔茨海默氏病的新型治疗靶标的跨学科方法”。大脑的衰老是老年人认知能力下降的原因，也是阿尔茨海默氏病（AD）的主要危险因素。尽管在疾病中具有核心作用，但对脑老化的分子基础以及从正常衰老到病理衰老的过渡却鲜为人知。该提案的总体目标是通过探索新确定的神经保护性调节网络的作用来获得对健康大脑衰老的新见解和向AD的过渡。我们最近发现，主要的发育调节剂REST/NRSF是在衰老的人脑中诱导的，并且与HDAC1一起辅助可以保护衰老神经元免受神经毒性应激，突触丧失和过度激发的基因网络的表达。该途径调节了衰老大脑中大量基因的表达，这些基因参与细胞死亡，炎症，氧化应激和AD病理学。诱导与在衰老期间的认知功能保留相关，而功能丧失与轻度认知障碍患者的认知能力下降有关。在AD中，受影响的大脑区域几乎完全消除了REST功能。我们的初步结果暗示了这种途径在调节衰老大脑，神经元和小胶质细胞中两种主要细胞类型中。该提案中的研究旨在阐明剩余网络在保护衰老神经元免受年龄相关的压力源，使用REST和HDAC1条件敲除小鼠的认知功能中，从而降低神经炎症并保留认知功能。新的高敏性转录组测序技术以及使用个人基因组项目工具的信息分析将用于定义受调节的基因网络。通过将这种系统遗传学方法应用于宗教秩序研究中良好的人脑样本中，我们将尝试定义预测成功衰老，早期认知下降和AD的静止调节基因网络。一个核心问题是该基因网络如何系统地在发展AD的个体中失败，以及该下降是否可以逆转。可以通过使用已知药物刺激Wnt信号传导以及新鉴定的小分子剂来激活REST的发现提出了令人兴奋的可能性，即可以通过基于REST网络激活的新型治疗方法来保护衰老的大脑。这些研究将汇集三名主要研究人员和许多与多学科方法的专业知识不同但互补领域的合作者，以了解从正常的大脑衰老到AD的过渡。