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: 8696452
• 负责人: Steven Estus
• 金额: $ 30.65万
• 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/8696452
• 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; Human; Immunoglobulins; In Vitro; Individual; Lectin; Length; Ligands; Mediator of activation protein; Messenger RNA; Microglia; Minor; Molecular; Mus; Mutate; NR0B2 gene; Neurons; Odds Ratio; PTPN11 gene; Phagocytosis; Pharmaceutical Preparations; Preventive; Process; Production; Protein Isoforms; Proteins; Public Health; RNA Splicing; Relative (related person); 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; novel; novel therapeutics; pre-clinical; public health relevance; receptor; sulfated glycoprotein 2; 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）：该提案的首要主题是，最近阿尔茨海默氏病（AD）全基因组关联研究鉴定的多态性从生物学上定义了 AD 途径中的限速步骤。因此，阐明其作用机制将确定强大的药理学靶点。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%，但对同一靶标作用强烈的药物可能会对 AD 风险产生很大影响。该提案将阐明 rs3865444 (rs444)（CD33 中与 AD 相关的 SNP）的作用机制，并将该机制转化为 AD 治疗的概念验证。在我们非常引人注目的初步结果中，我们将 rs444 的 AD 保护性小等位基因与 (i) 缺乏外显子 2 (D2-CD33) 的 CD33 比例的强劲增加联系起来，外显子 2 (D2-CD33) 似乎对 CD33 功能至关重要。大型制药公司已开发出针对急性髓系白血病（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。这引出了我们的总体假设：无论 CD33 抑制是由于遗传还是药物因素，CD33 功能降低都会降低 AD 风险。为了检验我们的假设，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 遗传学转化为新型 AD 治疗模拟物。总体而言，这一重点提案将开发我们令人信服的机制遗传结果，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。在超出本重点提案范围的工作中，我们预计这些治疗剂将在“AD”小鼠模型中进行测试，这些模型对人类 CD33 进行转基因，并最终在人类中进行测试。