Translating CD33 genetic mechanism into a novel Alzheimers therapeutic

描述（由申请人提供）：本提案的总体主题是，最近的阿尔茨海默病（AD）全基因组关联研究发现的多态性在生物学上定义了AD通路中的限速步骤。因此，阐明它们的作用机制将确定强有力的药理学靶点。值得注意的是，具有适度分子作用的SNP可能会将AD风险降低10%，但在同一靶标上起强烈作用的药物可能会对AD风险产生很大影响。本研究将阐明CD33中AD相关SNP rs3865444 （rs444）的作用机制，并将该机制转化为AD治疗的概念验证。在我们非常引人注目的初步结果中，我们将rs444的ad保护小等位基因与(i)缺乏外显子2 （D2-CD33）的CD33比例的显著增加联系起来，这似乎对CD33功能至关重要。大型制药公司已经开发出针对急性髓性白血病（AML）的CD33人源化单克隆抗体；这些抗体及其衍生物作为CD33拮抗剂具有潜在的AD相关性。这导致了我们的总体假设：无论CD33抑制是由于遗传还是药物作用，CD33功能降低都会降低AD风险。为了验证我们的假设，我们将(i)阐明CD33 AD SNP的潜在机制，（ii）比较CD33和D2- CD33的功能，特别是与AD致病机制相关的功能，以及（iii）将CD33遗传学转化为新的AD治疗模拟物。总的来说，这一重点提案将发展我们令人信服的机制遗传学结果，阐明D2-CD33和CD33功能的差异，并开始将这些变化转化为ad预防剂。在这一重点提案范围之外的工作中，我们预计这些治疗药物将在“AD”小鼠模型中进行测试，这些小鼠模型是人类CD33的转基因，并最终用于人类。

DESCRIPTION (provided by applicant): The overarching theme of this proposal is that polymorphisms identified by recent Alzheimer's disease (AD) genome wide association studies biologically define rate-limiting steps in AD pathways. Hence, elucidating their mechanism of action will identify robust pharmacologic targets. Notably, a SNP with modest molecular actions may reduce AD risk by 10% but a drug that acts strongly at the same target may have a large effect on AD risk. This proposal will elucidate the mechanism of action of rs3865444 (rs444), an AD-associated SNP in CD33, and translate this mechanism into a proof of concept AD treatment. In our highly compelling preliminary results, we associate the AD-protective minor allele of rs444 with (i) a robust increase in the proportion of CD33 lacking exon 2 (D2-CD33) which appears critical to CD33 function. Large pharma have developed humanized monoclonal antibodies against CD33 for acute myeloid leukemia (AML); these antibodies and their derivatives have potential AD relevance as CD33 antagonists. This leads to our global hypothesis: Reduced CD33 function decreases AD risk whether CD33 inhibition is due to genetics or pharmacologic agents. To test our hypothesis, we will (i) Elucidate the mechanism underlying the CD33 AD SNP, (ii) Compare CD33 and D2- CD33 function, especially relative to AD pathogenic mechanisms, and (iii) Translate CD33 genetics into a novel AD therapeutic mimic. Overall, this focused proposal will develop our compelling mechanistic genetic results, elucidate the differences in D2-CD33 and CD33 function, and begin to translate these changes into an AD-preventive agent. In work beyond the scope of this focused proposal, we anticipate that these therapeutic agents will be tested in "AD" murine models that are transgenic for human CD33 and, eventually, humans.