Chemical Tools to Target TREM2 in Alzheimer's Disease

项目总结/摘要 最近的全基因组关联研究和使用阿尔茨海默病（AD）小鼠模型的研究表明， 确定了一种小胶质细胞受体TREM 2（髓样细胞2上表达的触发受体）作为一种新的治疗药物， AD的目标。为了开发有效的治疗策略，对TREM 2的全面机制理解 功能是必需的。然而，由于与TREM 2相关的复杂性和缺乏 研究工具。虽然有许多遗传学工具，但很少有化学生物学工具被开发出来 研究TREM 2生物学长期的研究目标是了解TREM 2的详细机制 在AD发病机制中的作用，并确定新的治疗靶点和策略。的主要目标 本发明的目的是开发研究TREM 2糖基化的化学生物学工具，鉴定sTREM 2的受体， 探讨TREM 2的激活机制。这一目标将通过三个目标来实现。要求1 是开发一种稳健合成方法来产生具有同质聚糖的TREM 2胞外域，并检查 糖基化对TREM 2折叠、稳定性和与其配体结合的影响。目标2：开发sTREM 2 具有用于蛋白质交联的光反应基团的探针和用于亲和纯化的富集标签。这些 将应用探针来鉴定sTREM 2受体。目的3是开发限制性肽以结合和 激活TREM 2信号传导，允许对TREM 2激活的机制理解。该提案具有创新性 因为1）通过末端唾液酸化改变糖基化模式可以影响TREM 2的创新假设 功能，挑战TREM 2糖基化的现有观点，2）它将产生几种新的化学生物学 为科学界研究TREM 2提供了工具。该提案意义重大，因为1）它将增加 我们对复杂TREM 2生物学的理解，2）它将识别sTREM 2受体，一种潜在的新的 它将产生TREM 2的受约束的肽激动剂，其可以进一步优化 作为临床前测试的候选药物。

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.