Translating CD33 genetic mechanism into a novel Alzheimers therapeutic

描述(由申请人提供)：这项建议的主要主题是，最近的阿尔茨海默病(AD)全基因组关联研究确定的多态从生物学上定义了AD途径中的限速步骤。因此，阐明它们的作用机制将确定强大的药理靶点。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%，但对同一靶点作用强烈的药物可能会对AD风险产生很大影响。这一建议将阐明CD33中与AD相关的SNP rs3865444(Rs444)的作用机制，并将这一机制转化为AD治疗概念的证明。在我们非常有说服力的初步结果中，我们将rs444的AD保护性次要等位基因与(I)CD33缺失外显子2(D2-CD33)的比例显著增加相关联，而外显子2似乎对CD33的功能至关重要。大型制药公司已经开发出针对急性髓系白血病(AML)的人源化CD33单抗；这些抗体及其衍生物作为CD33拮抗剂具有潜在的AD相关性。这导致了我们的全球假说：无论CD33抑制是由于遗传学还是药物原因，CD33功能降低都会降低AD的风险。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，特别是相对于AD的致病机制，以及(Iii)将CD33遗传学转化为一种新的AD治疗模拟。总体而言，这一重点建议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预防药物。在这一重点提案范围之外的工作中，我们预计这些治疗剂将在人类CD33转基因小鼠模型上进行测试，并最终在人类身上进行测试。

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.