Translating CD33 genetic mechanism into a novel Alzheimers therapeutic

将 CD33 遗传机制转化为新型阿尔茨海默病治疗方法

• 批准号: 9038210
• 负责人: Steven Estus
• 金额: $ 30.75万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038210
• 关键词: Acute Myelocytic Leukemia; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; Antibodies; Apolipoprotein E; Apoptotic; Asses; Binding; Brain; Critical Pathways; Exons; Fab Immunoglobulins; Family member; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Half-Life; Health; Human; Immunoglobulins; In Vitro; Individual; Lectin; Length; Ligands; Mediator of activation protein; Messenger RNA; Microglia; Minor; Molecular; Mutate; NR0B2 gene; Neurons; Odds Ratio; PTPN11 gene; Phagocytosis; Pharmaceutical Preparations; Preventive; Process; Production; Protein Isoforms; Proteins; Public Health; RNA Splicing; Reporting; Sialic Acids; Signal Transduction; Single Nucleotide Polymorphism; Staging; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; Translating; Work; cohort; cytokine; genome wide association study; humanized monoclonal antibodies; in vivo; inhibitor/antagonist; mouse model; novel; novel therapeutics; pre-clinical; receptor; sulfated glycoprotein 2; targeted agent; transcription activator-like effector nucleases; uptake

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.

描述（由申请人提供）：该提案的总体主题是，最近阿尔茨海默氏病（AD）基因组广泛关联研究确定的多态性研究在生物学上定义了AD途径中的限制步骤。因此，阐明其作用机理将确定强大的药理目标。值得注意的是，具有适度分子作用的SNP可能会使AD风险降低10％，但是在同一目标上强烈起作用的药物可能对AD风险产生很大影响。该提案将阐明CD33中与AD相关的SNP的RS3865444（RS444）的作用机理，并将这种机制转化为概念AD处理的证明。在我们高度引人注目的初步结果中，我们将RS444的AD保护次要等位基因与（i）缺乏外显子2（D2-CD33）的CD33的比例有强劲增加，这对CD33功能似乎很重要。大型药物已经开发了针对急性髓样白血病（AML）的CD33的人性化单克隆抗体；这些抗体及其衍生物与CD33拮抗剂具有潜在的AD相关性。这导致了我们的全球假设：CD33功能降低会降低AD风险，无论CD33抑制是由于遗传学还是药理剂。为了检验我们的假设，我们将（i）阐明CD33 AD SNP的基础机制，（ii）比较CD33和D2-CD33功能，尤其是相对于AD致病机制，以及（iii）将CD33遗传学转化为一种新型的AD疗法模仿。总体而言，这项集中的建议将发展我们引人注目的机械遗传结果，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。在此重点提案的范围之外的工作中，我们预计这些治疗剂将在“ AD”鼠模型中进行测试，这些模型是人类CD33的转基因，最终是人类。