Chemical Tools to Target TREM2 in Alzheimer's Disease

靶向 TREM2 治疗阿尔茨海默病的化学工具

• 批准号: 10869791
• 负责人: Haifan Wu
• 金额: $ 5万
• 依托单位: WICHITA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10869791
• 关键词: Affect; Affinity Chromatography; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Binding; Biology; Chemicals; Communities; Complex; Development; Genetic; Goals; Ligands; Methods; Pathogenesis; Pattern; Peptides; Persons; Polysaccharides; Preclinical Testing; Research; Signal Transduction; TREM2 gene; drug candidate; genome wide association study; glycosylation; innovation; mouse model; new therapeutic target; novel; protein crosslink; receptor; sialylation; therapeutic target; therapeutically effective; tool

PROJECT SUMMARY/ABSTRACT Recent genome-wide association studies and studies using mouse models of Alzheimer’s disease (AD) have identified a microglial receptor TREM2 (triggering receptor expressed on myeloid cells 2) as a new therapeutic target of AD. To develop effective therapeutic strategies, a comprehensive mechanistic understanding of TREM2 functions is needed. However, it has been challenging due to the complexity associated with TREM2 and a lack of research tools. Although many genetic tools are available, few chemical biology tools have been developed to study TREM2 biology. The long-term research goal is to understand the detailed mechanism of TREM2 functions during AD pathogenesis and identify novel therapeutic targets and strategies. The main objective of this proposal is to develop chemical biology tools to study TREM2 glycosylation, identify the receptor of sTREM2, and investigate the activation mechanism of TREM2. This objective will be accomplished with three aims. Aim 1 is to develop a robust synthetic method to produce TREM2 ectodomain with homogenous glycans and examine the effect of glycosylation on TREM2 folding, stability, and binding to its ligands. Aim 2 is to develop sTREM2 probes with photo-reactive groups for protein cross-linking and enrichment tags for affinity purification. These probes will be applied to identify the sTREM2 receptor. Aim 3 is to develop constrained peptides to bind and activate TREM2 signaling, allowing a mechanistic understanding of TREM2 activation. The proposal is innovative because 1) innovative hypothesis that altered glycosylation patterns by terminal sialylation can affect TREM2 functions, challenging the existing view of TREM2 glycosylation and 2) it will yield several novel chemical biology tools available to the scientific community to study TREM2. The proposal is significant because 1) it will increase our understanding of the complex TREM2 biology, 2) it will identify a sTREM2 receptor, a potential new therapeutic target of AD, and 3) it will yield constrained peptide agonists of TREM2 that can be further optimized as drug candidates for preclinical testing.

项目摘要/摘要 使用阿尔茨海默氏病小鼠模型（AD）的最新基因组关联研究和研究 将小胶质细胞受体trem2（在髓样细胞上表达的触发受体2）确定为一种新疗法 AD的目标。为了制定有效的治疗策略，对TREM的全面理解2 需要功能。但是，由于与trem2相关的复杂性和缺乏，它受到了挑战 尽管有许多遗传工具，但很少开发化学生物学工具 研究TREM2生物学。长期的研究目标是了解TREM的详细机制2 AD发病机理期间的功能并确定新颖的治疗靶标和策略。主要目标 该建议是开发化学生物学工具来研究trem2糖基化，确定streem2的接收器， 并研究TREM2的激活机制。这个目标将以三个目标来实现。目标1 是开发一种可靠的合成方法来产生用同质聚糖产生trem2 eTodobain并检查 糖基化对TREM2折叠，稳定性和与其配体结合的影响。目标2是开发streem2 蛋白质交联和富集标签的光反应组问题。这些 问题将用于识别Strem2受体。目标3是开发约束的约束和 激活TREM2信号传导，从而可以对TREM2激活有机械理解。该提议是创新的 因为1）创新的假设，即通过终末lylation改变糖基化模式会影响trem2 功能，挑战现有的TREM2糖基化观点，2）它将产生几种新型的化学生物学 科学界可用的工具可以研究TREM2。该提议很重要，因为1）它将增加 我们对复杂TREM2生物学的理解，2）它将识别出streem2受体，这是一种潜在的新型 AD的治疗靶标，3）它将产生可进一步优化的TREM2的受限肽激动剂 作为临床前测试的候选药物。