权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetic determinants of a synuclein and tau

突触核蛋白和 tau 蛋白的遗传决定因素

基本信息

批准号：
8550144
负责人：
DENNIS WILLIAM DICKSON
金额：
$ 17.88万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8550144
关键词：
Age Age of Onset Alzheimer&apos s Disease Amygdaloid structure Area Autopsy Basal Nucleus of Meynert Basis pontis Biochemical Biological Markers Brain Brain Stem Cessation of life Clinical Collaborations Data Databases Dementia Dentate nucleus Diagnosis Frontal gyrus Funding Genes Genetic Genetic Determinism Genetic Risk Genetic Variation Grouping Haplotypes Image Analysis Immunohistochemistry Individual Lead Lesion Lewy Bodies Lewy Body Disease Measures Mediating Meta-Analysis Molecular Molecular Biology Motor Cortex Neurofibrillary Tangles Neurons Paralysed Parkinson Disease Parkinsonian Disorders Pathologic Pathology Phenotype Population Progressive Supranuclear Palsy Research Resources Risk Factors Sample Size Single Nucleotide Polymorphism Staging Structure of subthalamic nucleus Structure of superior frontal gyrus Substantia nigra structure Superior temporal gyrus Tauopathies Testing Tyrosine 3-Monooxygenase Validation Variant Western Blotting alpha synuclein base caudate nucleus clinical phenotype density digital falls frontal lobe genetic variant genome wide association study hindbrain illness length inclusion criteria insight novel protein aggregate putamen risk variant sex synucleinopathy tau Proteins trait

项目摘要

Project 2 will use intemnediate pathologic phenotypes to explore associations with genetic variants in progres- sive supranuclear palsy (PSP) and Lewy body disease (LBD). The results will provide insights into the molecular underpinnings of Parkinsonian disorders. We will use MAPT, as well as non-M(4PT single nucleotide polymor- phisms (SNPs) from genome-wide association studies (GWAS). Aim 1. Generate intermediate pathologic phenotypes for PSP. We will measure burden of tau using digital imaging in superior frontal gyrus, motor cortex, amygdala, caudate nucleus, pontine base and cerebellar dentate nucleus; microgliosis with IBA-1 immunohisto- chemistry in subthalamic nucleus and substantia nigra. We will record clinical phenotypes (sex, diagnosis, age at onset, age at death, disease duration), pathologic groupings (typical PSP vs. atypical PSP; pure PSP vs. mixed PSP), semi-quantitative scores of neuronal, astrocytic and oligodendroglial lesion density, biochemical characte- rization of tau from Western blots of caudate nucleus, and estimated latent trait variables constructed from the semiquantitative lesion scores. Aim 2. Assess association of intermediate pathologic phenotypes with gene variants in PSP. We will focus on 2 AMPT SNPs and 23 non-MAPT SNPs that achieved p<1x10'^ in the PSP GWAS. Each SNP will be tested for association in more than 700 PSP cases against 5 primary pathologic phe- notypes. We hypothesize that intermediate pathologic phenotypes, a large sample size and targeted SNPs will be powerful in identifying mechanisms of genetic risk variants in PSP. Aim 3. Generate intermediate patholog- ic phenotypes for LBD. We will measure burden of a-synuclein, A3, and tau in mid-frontal gyrus, superior tem- poral gyrus, amygdala and putamen; tyrosine hydroxylase immunohistochemistry of putamen; and microgliosis in substantia nigra and basal nucleus of Meynert. We will record clinical phenotypes (as for PSP, but also dementia and/or Parkinsonism), pathological phenotypes (brainstem, transitional, or diffuse LBD; pure LBD vs. mixed LBD) as well as Lewy body counts in 5 cortical areas and the amygdala. We will estimate latent trait variables underly- ing the semiquantitative scores of LBs, plaques and tangles as in Aim 1. Aim 4. Assess association of inter- mediate pathologic phenotypes with gene variants from PD GWAS. SNPs will be identified as top hits from the autopsy PD GWAS. We will focus on 2 MAPT SNPS and 23 non-/W>!\P7SNPs that achieved p<1x10'(R). Each SNP will be tested for association with 9 intermediate phenotypes in more than 700 LBD cases. Ultimately, ge- netic and phenotypic data on a large number of PSP and LBD brains will not only provide mechanistic insight, but also be a resource for Udall Center collaborators and for others.

项目2将使用中间病理表型来探索进展中的遗传变异的关联