Role of the TOMM40 poly-T variant in the pathogenesis of Alzheimer's disease

TOMM40多聚T变体在阿尔茨海默病发病机制中的作用

• 批准号: 8439989
• 负责人: ALLEN D ROSES
• 金额: $ 41.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439989
• 关键词: Affect; Age; Age of Onset; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; American; Animal Model; Animals; Autopsy; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Blood Vessels; Brain; Brain region; Caregivers; Caring; Cells; Cerebrospinal Fluid; Chromosomes; Chromosomes, Human, Pair 7; Clinical Trials; Cost of Illness; Dementia; Disease; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Haplotypes; Homozygote; Human; Impaired cognition; Intervention; Introns; Knowledge; Late Onset Alzheimer Disease; Lead; Length; Link; Linkage Disequilibrium; Measures; Mediating; Medical; Medicare; Messenger RNA; Modeling; Molecular; Molecular Biology; Molecular Profiling; Mus; Neuroglia; Neurons; Onset of illness; Organ; Outcomes Research; Outer Mitochondrial Membrane; Pathogenesis; Pathway interactions; Patients; Poly T; Population; Predisposition; Preventive; Process; Productivity; Proteins; Publishing; Regulation; Reporter; Reporting; Resources; Risk; Role; Sampling; Senile Plaques; Signal Transduction; Site; Slice; System; Testing; Therapeutic; Tissues; Transcript; Transgenic Mice; Up-Regulation; Validation; Variant; Work; aged; base; cost; density; drug candidate; genetic risk factor; genome wide association study; gray matter; high risk; improved; mouse model; pre-clinical; prevent; promoter; public health relevance; research clinical testing; screening; tau-1; therapeutic target; translocase; trend

DESCRIPTION (provided by applicant): We have demonstrated that there is a strong association between polymorphic poly-T variant of TOMM40 and the age of onset of late-onset Alzheimer's disease (AD). For APOE e3/4 patients who develop AD, those with long poly-T repeats linked to APOE e3 developed AD on average 7 years earlier than those with shorter poly-T polymorphisms linked to APOE e3. We have replicated this finding in a distinct population. In APOE e3/e3 homozygotes there is also a significant correlation between the length of the poly-T variant and grey matter density, which is independent of APOE e4. TOMM40 is in linkage disequilibrium with APOE and encodes the protein Translocase of the Outer Mitochondrial Membrane. Our central hypothesis is that the poly-T tract controls expression of TOMM40 and APOE in brain, and thus regulates the pathways in which these proteins participate. We will test this hypothesis at the genomic, genetic and biochemical levels. We will precisely identify the long, short and the ancestral poly-T tracts, and correlate the age o onset of AD and AD risk to these alleles. We will test our working model that the poly-T tract regulates TOMM40 and APOE expression by measuring APOE and TOMM40 mRNA and protein levels in rapidly autopsied human brain samples, and correlate these changes with susceptibility to AD-related damage across different brain regions. We will also construct two humanized mouse models of the TOMM40-APOE linkage disequilibrium region, that will permit more detailed, mechanism-based studies of the regulation of expression of these genes. We will exchange the mouse TOMM4-APOE linkage disequilibrium region with the homologous human region. Both models will be made homozygous for human APOE e3, thus eliminating possible confounding effects of APOE e4, and we will make one homozygous for the short poly-T polymorphism while we will make the other homozygous for the long poly-T variant. Successfully fulfilling these aims will advance our understanding of the molecular mechanisms underlying the genetic risk factors in AD and will provide valuable pathways for developing an effective preventive therapy for late-onset Alzheimer's disease.

描述（由申请人提供）：我们已经证明TOMM 40的多态性多聚T变体与晚发性阿尔茨海默病（AD）的发病年龄之间存在强关联。对于发生AD的APOE e3/4患者，与APOE e3相关的长poly-T重复序列的患者比与APOE e3相关的短poly-T多态性的患者平均早7年发生AD。我们在一个不同的人群中复制了这一发现。在APOE e3/e3纯合子中，多聚T变异体的长度与灰质密度之间也存在显著相关性，这与APOE e4无关。TOMM 40与APOE连锁不平衡，编码线粒体外膜转位酶蛋白。我们的中心假设是多聚T束控制TOMM 40和APOE在脑中的表达，从而调节这些蛋白质参与的通路。我们将在基因组、遗传和生物化学水平上检验这一假设。我们将精确地识别长、短和祖先多聚T束，并将AD发病年龄和AD风险与这些等位基因相关联。我们将通过测量快速尸检人脑样本中的APOE和TOMM 40 mRNA和蛋白水平来测试我们的工作模型，即多聚T束调节TOMM 40和APOE表达，并将这些变化与不同脑区对AD相关损伤的易感性相关联。我们还将构建TOMM 40-APOE连锁不平衡区的两个人源化小鼠模型，这将允许对这些基因的表达调控进行更详细的基于机制的研究。我们将小鼠TOMM 4-APOE连锁不平衡区与同源人区交换。两种模型都将是人APOE e3纯合的，从而消除了APOE e4可能的混杂效应，我们将使一种纯合的短聚T多态性，而另一种纯合的长聚T变体。成功实现这些目标将促进我们对AD遗传风险因素的分子机制的理解，并为开发有效的预防性治疗晚发性阿尔茨海默病提供有价值的途径。