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

基本信息

批准号：
9883697
负责人：
Timothy J Hohman
金额：
$ 85.31万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883697
关键词：
AD transgenic mice Affinity Chromatography Aging Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease pathology 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 Genes Genetic Genetic Markers Genomics Genotype Goals Hippocampus (Brain)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 Patients Peripheral Pharmacology 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 base brain tissue cerebral atrophy cohort data resource design falls innovation multidisciplinary neuropathology neuroprotection novel protein expression receptor religious order study resilience response stem cells targeted treatment therapeutic target tool ward

项目摘要

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.

抽象的血管内皮生长因子 (VEGF) 是一种与预防血管内皮细胞损伤有关的蛋白质。阿尔茨海默病（AD）。脑脊液 (CSF) VEGF 水平高与生长速度减慢相关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患有高水平 AD 神经病理学的个体中尤其强，表明 VEGF 可以预防 AD 的临床后果。事实上，当用干细胞表达VEGF后，与AD相关的记忆缺陷得以逆转。然而，发展由于大量生物过程受到 VEGF 的影响，VEGF 作为治疗靶点受到了限制。 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（神经毡蛋白）基因。这组不同的配体和受体之间的相互作用驱动截然不同的信号级联。这种生物变异提供了一个令人兴奋的机会来质疑通过靶向基因组学和蛋白质组学研究各种 VEGF 途径。该提案将寻求确定 VEGF 信号分子最有力地预测神经保护作用，并阐明神经保护作用背后的途径 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，利用人类来自特征明确的衰老纵向队列研究的样本，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来执行这一详细的利用阿尔茨海默病恢复力 (RAD) 数据库分析 VEGF 信号传导，包括跨 8 个大型 AD 队列研究的协调且经过验证的连续弹性指标。在 RAD，我们量化了个体对与以下相关的认知缺陷的适应程度 AD 神经病理学，提供理想的表型来评估 VEGF 的作用。 RAD 包括基因型数据 (n=3037)、脑组织基因表达数据 (n=588) 以及获取存储的脑组织新颖的蛋白质组分析（n=1433）。该提案将首先对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主要与恢复力密切相关。第二，我们将进行详细的蛋白质组分析，对所有 VEGF 进行全面测量配体和受体蛋白质组，包括翻译后修饰，以阐明 VEGF 在大脑中的作用蛋白质水平。最后，我们将利用该提案生成的丰富 VEGF 信号数据来识别沿着同一信号通路的额外的恢复力遗传标记。有关的知识最有力预测恢复力的机制、信号通路和 VEGF 的特定形式加速 VEGF 信号分子作为药物干预靶标的开发。