Drugs repositioning to target TREM2 in Alzheimer disease

TREM 2中的单个氨基酸变体已通过全基因组关联研究鉴定为以下变体之一： 是晚发性阿尔茨海默病（AD）最强的遗传风险因素。TREM 2中的AD相关变体 削弱TREM 2结合和响应体内配体的信号传导能力，进一步影响TREM 2介导的 AD中的免疫激活。识别作为TREM 2配体的可用药物，并了解药物 调节TREM 2介导的免疫激活，可以重新定位可用的药物靶向TREM 2， 联合药物治疗AD的进展。这项研究的核心假设是 可获得的药物，包括FDA批准的药物，可以以碱性和/或碱性结合TREM 2。 疏水结合位点，药物在TREM 2的任一或两个结合位点上的变构效应可调节配体 在两个位点结合以调节AD中TREM 2介导的免疫活化，并补偿 通过AD相关TREM 2变体的TREM 2介导的免疫活性。我们将用三个例子来检验这个假设。 目标是综合计算和实验方法。目的1是确定可用的药物结合 TREM 2上的碱性或/和疏水性结合位点， 生物学实验验证目的2是表征可用药物与TREM 2的相互作用 并确定在碱性和疏水性TREM 2结合位点结合的可用药物的变构效应， 和TREM 2介导的免疫活化。目的3是确定可用的药物是否结合TREM 2 可以抵消AD引起的TREM 2-ApoE结合及其介导的免疫活性的丧失。 相关TREM 2变体。从这项研究中获得的新知识可能对AD产生很大影响 通过重新定位现有药物以靶向TREM 2进行研究和治疗， 调节TREM 2介导的免疫激活的可用药物，为策略提供分子基础 开发使用可用的药物，包括药物组合以靶向TREM 2用于AD治疗。 在基础水平上研究AD中新的TREM 2功能机制， 在碱性和/或疏水性位点的可用药物，以及可用药物是否以及如何补偿 由AD相关变体引起的TREM 2免疫活性的丧失是必要的第一步。研究创新 包括：1）这将是第一项通过靶向TREM 2和TREM 2受体来鉴定可用药物作为TREM 2配体的研究。 碱性和疏水性位点，以更确定的方式进行无偏倚的虚拟筛选和验证， 生物物理结合和生物细胞功能实验。2)这项研究的结果将揭示新的 关于在任一TREM 2结合位点结合的可用药物对TREM 2结合的变构效应的发现 AD病理学相关的配体在体内包括ApoE，并对TREM 2介导的免疫激活起作用。第三章 研究结果可以提出用目前用于其他疾病的现有药物靶向TREM 2， 通过AD相关变体补偿TREM 2介导的免疫活性的损失用于AD治疗。

Single amino acid variants in TREM2 have been identified by genome-wide association studies to be one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). AD-associated variants in TREM2 impair TREM2's ability to bind and signal in response to ligands in the body, further affecting TREM2-mediated immune activation in AD. Identifying the available drugs as TREM2 ligands and understanding how the drugs regulate TREM2-mediated immune activation, could reposition the available drugs to target TREM2 and aid the development of combined drug therapy for AD treatment. The central hypothesis of the proposed study is that the available drugs, including FDA-approved drugs, could bind TREM2 at either basic and/or hydrophobic binding site, allosteric effect of drugs at TREM2 either or two binding sites could regulate ligand binding at both sites to modulate TREM2-mediated immune activation in AD, and compensate for the loss of TREM2-mediated immune activities by AD-associated TREM2 variants. We will test the hypothesis with three Aims with integrated computational and experimental approaches. Aim 1 is to identify available drugs bound basic or/and hydrophobic binding sites on TREM2 with unbiased virtual screening and biophysical and biological experimental validation. Aim 2 is to characterize the interactions of the available drugs with TREM2 and determine the allosteric effect of available drugs binding at basic and hydrophobic TREM2 binding sites, and on TREM2-mediated immune activation. Aim 3 is to determine whether the available drugs bound TREM2 could counteract the loss of TREM2-ApoE binding and its mediated immune activities caused by AD- associated TREM2 variants. New knowledge gained from this study could have high impact for AD research and treatment by repositioning the available drugs to target TREM2 and further the insight into available drugs modulating TREM2-mediated immune activation, offering a molecular basis for strategy development of using available drugs including drug combinations to target TREM2 for AD treatment. Investigating novel TREM2 functional mechanism in AD at a fundamental level  how TREM2 activation by available drugs at basic and/or hydrophobic sites and whether and how available drugs compensate for the loss of TREM2 immune activity by AD-associated variants  is the necessary first step. Innovations of study include: 1) This will be the first study to identify available drugs as TREM2 ligand by targeting both TREM2 basic and hydrophobic sites in a more conclusive manner with unbiased virtual screening and validation with biophysical binding and biological cellular function experiments. 2) Results from this study will unveil novel findings about the allosteric effects of available drugs binding at either TREM2 binding site, on TREM2 binding AD pathology related ligand in the body including ApoE, and on TREM2-mediated immune activation. 3) Research outcomes could propose targeting TREM2 with available drugs currently used for other conditions to compensate for loss of TREM2-mediated immune activities by AD-associated variants for AD treatment.