Understanding the role of Eph signaling in Alzheimer's disease

了解 Eph 信号在阿尔茨海默病中的作用

• 批准号: 9892945
• 负责人: Andrew Alexander Sproul
• 金额: $ 24.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892945
• 关键词: Affect; African American; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-Protein; Autopsy; Binding; Biochemical; Biological; Biology; Brain; CRISPR/Cas technology; Caribbean Hispanic; Cell Cycle; Cell Proliferation; Cell model; Cell physiology; Cells; Chronic; Code; Collaborations; Complex; Data; Data Set; Developmental Process; Disease; Disease Pathway; Down-Regulation; EPHA1 gene; Engineering; Eph Family Receptors; Ephrins; Erythropoietin; Ethnic Origin; Exons; Family; Family Study; Follow-Up Studies; Functional disorder; Genes; Genomics; Goals; Hispanic Americans; In Vitro; Institutes; Knock-in; Knock-out; Late Onset Alzheimer Disease; Lead; Ligands; Light; Mediating; Metabolism; Mitotic; Molecular; Mus; Mutation; Nature; Neurons; Normal Cell; Pathogenesis; Pathway interactions; Patients; Phase; Physiological; Play; Pluripotent Stem Cells; Proteins; Receptor Activation; Receptor Gene; Receptor Protein-Tyrosine Kinases; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Stimulus; Synapses; Testing; Variant; Washington; axon guidance; base; behavioral impairment; brain tissue; case control; caucasian American; causal variant; cohort; data harmonization; differential expression; druggable target; exome; gain of function; genetic variant; genome wide association study; genome-wide; genomic locus; insight; member; next generation; novel; protein function; receptor; segregation; stem cell model; synaptogenesis; targeted sequencing; tau Proteins; therapeutic target; transcriptome sequencing; whole genome

PROJECT SUMMARY Late-onset Alzheimer’s disease (LOAD) is a genetically complex and thought to be influenced, at least in part, across a number of different loci. Genome-wide association studies (GWAS) have helped fill in the missing gaps, by uncovering several novel genes for LOAD. EPHA1, encoding for the EphA1 receptor, a member of the erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases was identified as a potential locus in a GWAS and subsequently causal mutations were found by us. Physiologically, the Eph receptor family regulates various developmental processes, especially in the CNS, controlling neuron maturation, axon guidance and synapse formation. Aberrant signaling by two members, EphA4 and EphB2, has been directly implicated in Aβ-mediated synaptic dysfunction and behavioral impairment. As for EphA1, the precise molecular nature of its involvement in AD remains uncertain. We find (preliminary data) that EphA1 levels may be upregulated in LOAD brain, suggesting that increased signaling may underlie one or more AD-associated changes. The mutation (P460L) we reported is a rare gain-of-function coding mutation for EphA1 supporting that conclusion. Together these results suggest a role for chronic activation of EphA1 in LOAD. This means that, of the 14 receptors in the Eph family, 3 have been associated with LOAD, either molecularly or genetically, hinting at a much larger and global role for Eph signaling in LOAD pathogenesis. The overall objective of this proposal is to understand the impact of altered function in specific Eph related genes and the related pathway, in particular variant-specific associations, expression and effect on LOAD pathogenesis. Given the importance of Eph genes in normal cell function, we hypothesize that coding mutations altering protein function, such as EphA1-P460L, will impact one or more downstream pathways involved in LOAD. Ultimately, understanding the function of the Eph-pathway may provide insight into the treatment of LOAD. We will harmonize existing next generation sequence datasets on multiplex Caribbean Hispanic, Caucasian and African American families and a multi-ethnic case-control set and test the association of Eph receptors with risk of LOAD. Subsequently, we will characterize the molecular mechanism(s) involved in altered function of identified Eph variants starting with EphA1-P460L how this contributes to LOAD pathogenesis.

项目摘要 晚发性阿尔茨海默病（LOAD）是一种遗传复杂的疾病，被认为至少部分受到 在许多不同的位点上。全基因组关联研究（GWAS）帮助填补了缺失的空白， 通过发现几个新的LOAD基因。EPHA 1，编码EphA 1受体，EphA 1受体的成员， 产生红细胞生成素的肝细胞（Eph）受体酪氨酸激酶家族被鉴定为潜在的 基因座中的GWAS和随后的因果突变被我们发现。生理上，Eph受体家族 调节各种发育过程，特别是在中枢神经系统中，控制神经元成熟，轴突导向 和突触的形成两个成员EphA 4和EphB 2的异常信号传导直接涉及 Aβ介导的突触功能障碍和行为障碍。至于EphA 1，其确切的分子性质是 参与AD仍不确定。我们发现（初步数据）EphA 1水平可能在LOAD中上调， 这表明增加的信号可能是一种或多种AD相关变化的基础。突变 （P460 L）是一种罕见的EphA 1功能获得性编码突变，支持了这一结论。一起 这些结果表明EphA 1的慢性激活在LOAD中的作用。这意味着，在14个受体中， Eph家族，3已经与LOAD相关，无论是分子上还是遗传上，暗示着一个更大的， Eph信号在LOAD发病机制中的全球作用。本提案的总体目标是了解 特定Eph相关基因和相关途径功能改变的影响，特别是变异特异性 关联、表达和对LOAD发病机制的影响。鉴于Eph基因在正常细胞中的重要性， 功能，我们假设改变蛋白质功能的编码突变，如EphA 1-P460 L，将影响一个 或更多下游通路参与LOAD。最终，了解Eph通路的功能 可以为LOAD的治疗提供见解。我们将协调现有的下一代序列数据集 在多个加勒比海西班牙裔、高加索人和非洲裔美国人家庭和多种族病例对照组中 并测试Eph受体与LOAD风险的关联。随后，我们将表征分子 涉及以EphA 1-P460 L开始的鉴定的Eph变体的功能改变的机制， 有助于LOAD发病机制。