Validation Studies of CRF Receptor 1 as a Target for AD

CRF 受体 1 作为 AD 靶点的验证研究

• 批准号: 9325287
• 负责人: Robert A Rissman
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325287
• 关键词: AD pathology; Acute; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid beta-Protein; Animals; Anxiety; Autopsy; Behavioral; Brain; Brain Diseases; CRF receptor type 1; Chronic; Chronic stress; Clinical; Cognitive; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dementia; Dependence; Development; Dimensions; Disease; Environmental Risk Factor; Event; FDA approved; Future; Genes; Genetic; Genetic Transcription; Genome; Hereditary Disease; Heritability; Hippocampus (Brain); Human; Impaired cognition; Individual; Intention; Knock-out; Lead; Link; MAPT gene; Mediator of activation protein; Memory Loss; Memory impairment; Mus; Mutation; Nature; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuropeptides; Outcome Study; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Process; Proteome; Receptor Activation; Religion and Spirituality; Research; Research Project Grants; Risk; Risk Factors; Rodent; Rodent Model; Role; Senile Plaques; Severities; Signal Transduction; Signaling Molecule; Stress; System; Therapeutic; Therapeutic Intervention; Time; Tissue Banks; Tissues; Transgenic Organisms; Translational Research; Translations; Validation; Veterans; Work; age related; base; beta amyloid pathology; brain tissue; cognitive change; cohort; critical period; epidemiology study; experience; experimental study; extracellular; indexing; interest; mouse model; protein expression; psychological distress; public health relevance; receptor expression; repository; tau Proteins; tau phosphorylation; tau-1; therapeutic target; transcriptome; transcriptome sequencing; validation studies

 DESCRIPTION (provided by applicant): Project Summary/Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and impairments in other aspects of cognitive and behavioral function. It is the most common form of dementia, currently afflicting roughly five million Americans, a number projected to quadruple by 2050. Neuropathologically, AD is defined by the accumulation of extracellular plaques composed of beta-amyloid (Aβ), and intracellular neurofibrillary tangles (NFTs), consisting of phosphorylated forms of the microtubule- associated protein, tau. Mutations in three separate genes have been linked to the rare (<3% of cases), heritable, form of AD. The causes of the far more prevalent, sporadic, form are unknown, though recent work has implicated environmental factors, prominently including stress, as promoting AD pathogenesis. For example, recent epidemiological studies indicate that individuals prone to experience "psychological distress" or anxiety are at substantially greater risk to develop AD as age-matched controls that score low on this dimension. The overarching hypothesis of this proposal is that chronic stress exposure in humans confers increased risk of AD due to stress-associated alterations in the cortical and hippocampal CRF signaling systems. Based on our preliminary data, we propose that a potential mechanism underlying this stress-AD relationship is the modulation of Aβ by CRFR1 activation.

 描述（由申请人提供）： 项目摘要/摘要阿尔茨海默氏病 (AD) 是一种与年龄相关的神经退行性疾病，其特征是进行性记忆丧失以及认知和行为功能其他方面的损害。它是最常见的痴呆症，目前约有 500 万美国人受其困扰。预计到 2050 年将增加四倍。在神经病理学上，AD 的定义是由 β-淀粉样蛋白 (Aβ) 组成的细胞外斑块和细胞内神经原纤维缠结的积累(NFT)，由微管相关蛋白 tau 的磷酸化形式组成，三个独立基因的突变与罕见（<3% 的病例）、可遗传的 AD 形式有关。散发性的、形式尚不清楚，但最近的研究表明环境因素（主要包括压力）会促进AD的发病机制。例如，最近的流行病学研究表明，容易经历“心理困扰”或焦虑的个体的比例要高得多。该建议的总体假设是，由于皮质和海马 CRF 信号系统中与压力相关的变化，人类的长期压力暴露会增加患 AD 的风险。根据我们的初步数据，我们提出这种压力-AD 关系的潜在机制是 CRFR1 激活对 Aβ 的调节。