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: 9251728
• 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 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251728
• 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; Biological; Brain; Critical Pathways; Exons; Fab Immunoglobulins; Family member; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Half-Life; 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; Pathogenicity; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Preventive; Process; Production; Protein Isoforms; Proteins; Public Health; RNA Splicing; Reporting; Sialic Acids; Signal Transduction; Single Nucleotide Polymorphism; Staging; Testing; Therapeutic; Therapeutic Agents; Transgenic Model; Translating; Work; cohort; cytokine; genome wide association study; humanized monoclonal antibodies; in vivo; inhibitor/antagonist; mouse model; novel; novel therapeutics; pre-clinical; public health relevance; receptor; sulfated glycoprotein 2; targeted agent; 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）：本提案的总体主题是，最近阿尔茨海默病（AD）全基因组关联研究确定的多态性在生物学上定义了AD途径中的限速步骤。因此，阐明其作用机制将确定稳健的药理学靶点。值得注意的是，具有适度分子作用的SNP可以将AD风险降低10%，但是在相同靶点处强烈作用的药物可能对AD风险具有很大的影响。该提案将阐明rs3865444（rs 444）（CD 33中AD相关SNP）的作用机制，并将该机制转化为AD治疗的概念验证。在我们非常令人信服的初步结果中，我们将rs 444的AD保护性次要等位基因与（i）CD 33缺失外显子2（D2-CD 33）比例的稳健增加相关联，这对CD 33功能至关重要。大型制药公司已经开发了针对急性髓性白血病（AML）的CD 33的人源化单克隆抗体;这些抗体及其衍生物作为CD 33拮抗剂具有潜在的AD相关性。这导致了我们的总体假设：降低CD 33功能降低AD风险，无论CD 33抑制是由于遗传学还是药理学因素。为了验证我们的假设，我们将（i）阐明CD 33 AD SNP的潜在机制，（ii）比较CD 33和D2-CD 33功能，特别是相对于AD致病机制，（iii）将CD 33遗传学转化为新型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-CD 33和CD 33功能的差异，并开始将这些变化转化为AD预防剂。在超出本重点提案范围的工作中，我们预计这些治疗剂将在人CD 33转基因的“AD”鼠模型中进行测试，并最终在人类中进行测试。

项目成果

Genetics ignite focus on microglial inflammation in Alzheimer's disease.

• DOI: 10.1186/s13024-015-0048-1
• 发表时间: 2015-10-05
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Malik M;Parikh I;Vasquez JB;Smith C;Tai L;Bu G;LaDu MJ;Fardo DW;Rebeck GW;Estus S
• 通讯作者: Estus S