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

基本信息

批准号：
8676614
负责人：
ALLEN D ROSES
金额：
$ 48.59万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8676614
关键词：
Affect Age Age of Onset Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos 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

项目摘要

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，Tomm40的多态Poly-T变体与晚期发病的阿尔茨海默氏病（AD）之间存在很强的关联。对于开发AD的APOE E3/4患者，与APOE E3相关的长聚-T重复序列的患者平均比与APOE E3相关的poly-T多态性较短的患者早7年。我们已经在不同的人群中复制了这一发现。在APOE E3/E3纯合子中，多-T变体密度和灰质密度的长度之间也存在显着的相关性，这与APOE E4无关。 Tomm40与APOE不平衡，并编码外部线粒体膜的蛋白质易位酶。我们的中心假设是，多-T道控制了大脑中Tomm40和ApoE的表达，因此调节了这些蛋白质参与的途径。我们将在基因组，遗传和生化水平上检验该假设。我们将精确地确定长，短和祖先的聚-T段，并将AD和AD风险的年龄与这些等位基因相关联。我们将测试我们的工作模型，即通过测量快速动体体人脑样品中的APOE和TOMM40 mRNA和蛋白质水平来调节Tomm40和ApoE表达，并将这些变化与对不同大脑区域的AD相关损伤的敏感性相关。我们还将构建两种人性化小鼠模型的Tomm40-apoe连杆不平衡区域，这些模型将允许对这些基因表达的调节进行更详细的基于机制的研究。我们将将小鼠Tomm4-apoe连锁区域不平衡区域与同源人类区域交换。这两种模型均应使人APOE E3纯合，从而消除了APOE E4的可能混杂作用，并且我们将使一个纯合子对短多-T多态性纯合，而我们将使长poly-t变体使另一个纯合子。成功实现这些目标将提高我们对AD遗传危险因素背后的分子机制的理解，并将为开发有效的预防性治疗以针对阿尔茨海默氏病开发有效的预防疗法。