Neuroprotective Effects of Vascular Endothelial Growth Factor in Alzheimer's Disease

血管内皮生长因子对阿尔茨海默病的神经保护作用

• 批准号: 10613404
• 负责人: Timothy J Hohman
• 金额: $ 80.8万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613404
• 关键词: AD transgenic mice; Acceleration; Affinity Chromatography; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Biological; Biological Models; Biological Process; Brain; Cerebrospinal Fluid; Classification; Clinical; Cognitive; Cognitive deficits; Cohort Studies; Data; Databases; Development; Endothelial Growth Factors Receptor; Evaluation; Family; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genomics; Genotype; Goals; Hippocampus; Human; Immobilization; Impaired cognition; Implant; Individual; International; Intervention; Knowledge; Ligands; Longitudinal cohort study; Mass Spectrum Analysis; Measurement; Medicine; Memory; Memory impairment; Messenger RNA; Metals; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuropilins; Neuropsychology; Participant; Pathway Analysis; Pathway interactions; Peripheral; Phenotype; Phosphopeptides; Phosphorylation; Positioning Attribute; Post-Translational Protein Processing; Prefrontal Cortex; Protein Isoforms; Proteins; Proteolysis; Proteomics; RNA Splicing; Receptor Gene; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research Proposals; Resources; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Therapeutic Intervention; Tissues; Transcript; Variant; Vascular Endothelial Growth Factors; Work; angiogenesis; brain tissue; cerebral atrophy; cohort; data resource; design; falls; innovation; multidisciplinary; neuropathology; neuroprotection; novel; pharmacologic; protein expression; receptor; religious order study; resilience; response; stem cells; targeted treatment; therapeutic target; tool; ward

Abstract Vascular endothelial growth factor (VEGF) is a protein that has been implicated in protection against Alzheimer's disease (AD). High levels of cerebrospinal fluid (CSF) VEGF are associated with slower rates of cognitive decline and slower rates of brain atrophy. Furthermore, the neuroprotective effects of VEGF are particularly strong among individuals who are harboring high levels of AD neuropathology, suggesting VEGF may protect against the clinical consequences of AD. Indeed, when treating the hippocampus of AD mice with stem cells expression VEGF, the memory deficits associated with AD are reversed. Yet, the development of VEGF as a therapeutic target has been limited due to the large number of biological process impacted by VEGF signaling. The VEGF family consists of 5 ligand genes, 3 known tyrosine-kinase receptor genes, and 2 modulating receptor (neuropilins) genes. Interactions between this diverse set of ligands and receptors drive vastly different signaling cascades. Such biological variation provides an exciting opportunity to interrogate the various VEGF pathways through targeted genomics and proteomics. This proposal will seek to identify the VEGF signaling molecules that most strongly predict neuroprotection, and clarify the pathways that underly the beneficial effects of VEGF. We will leverage advanced genomic and proteomic approaches using human samples from well characterized longitudinal cohort studies of aging, with a particular focus on gene and protein expression in brain tissue. Our multi-disciplinary team is uniquely positioned to perform this detailed analysis of VEGF signaling by leveraging the Resilience from Alzheimer's Disease (RAD) database, which includes a harmonized and validated continuous metric of resilience across 8 large cohort studies of AD. In RAD, we have quantified the degree to which an individual is resilient to the cognitive deficits associated with AD neuropathology, providing the ideal phenotype to evaluate the effects of VEGF. The RAD includes genotype data (n=3037), gene expression data from brain tissue (n=588), and access to stored brain tissue for novel proteomic analyses (n=1433). This proposal will first perform a comprehensive analysis of VEGF ligand and receptor genes in brain tissue to identify which gene isoforms mostly strongly relate to resilience. Second, we will perform a detailed proteomic analysis in which we perform comprehensive measurement of all VEGF ligand and receptor proteoforms, including post-translational modifications, to clarify VEGF effects in brain at the protein level. Finally, we will leverage the rich VEGF signaling data generated from this proposal to identify additional genetic markers of resilience that fall along this same signaling pathway. Knowledge about the mechanisms, signaling pathways, and specific forms of VEGF that most strongly predict resilience will accelerate the development of VEGF signaling molecules as targets for pharmacological intervention.

摘要 血管内皮生长因子（VEGF）是一种蛋白质，其与抗肿瘤的保护作用有关。 阿尔茨海默病（AD）。高水平的脑脊液（CSF）VEGF与较慢的 认知能力下降和脑萎缩速度减慢。此外，VEGF的神经保护作用是 在AD神经病理学水平高的个体中尤其强烈，表明VEGF 可以预防AD的临床后果。事实上，当用药物治疗AD小鼠的海马时， 干细胞表达VEGF，与AD相关的记忆缺陷被逆转。然而， VEGF作为治疗靶点受到了限制，这是由于VEGF对许多生物学过程的影响。 VEGF信号传导。VEGF家族由5个配体基因、3个已知的酪氨酸激酶受体基因和2个 调节受体（神经纤毛蛋白）基因。这些不同的配体和受体之间的相互作用 截然不同的信号级联。这种生物学变异提供了一个令人兴奋的机会， 通过靶向基因组学和蛋白质组学研究多种VEGF途径。这项建议将设法查明 VEGF信号分子，最强有力地预测神经保护，并澄清了基础的途径， VEGF的有益作用我们将利用先进的基因组学和蛋白质组学方法， 样本来自老化的纵向队列研究，特别关注基因和 脑组织中的蛋白质表达。我们的多学科团队具有独特的优势，可以执行此详细的 通过利用阿尔茨海默病恢复力（RAD）数据库分析VEGF信号传导， 包括在8项大型AD队列研究中协调和验证的持续弹性指标。在 RAD，我们已经量化了一个人对与之相关的认知缺陷的适应程度， AD神经病理学，提供了理想的表型，以评估VEGF的影响。RAD包括 基因型数据（n=3037），来自脑组织的基因表达数据（n=588），以及对存储的脑组织的访问， 新的蛋白质组学分析（n=1433）。本建议首先对VEGF配体进行全面分析， 和脑组织中的受体基因，以确定哪些基因亚型与恢复力密切相关。第二、 我们将进行详细的蛋白质组学分析，其中我们对所有VEGF进行全面测量， 配体和受体蛋白形式，包括翻译后修饰，以阐明VEGF在脑中的作用， 蛋白质水平。最后，我们将利用该提案产生的丰富的VEGF信号转导数据， 另外的适应性遗传标记也会沿着沿着这条信号通路。的知识 机制，信号通路和VEGF的特定形式，最强烈地预测弹性将 加速VEGF信号分子作为药物干预靶点的发展。