Identification of genetic risk factors that predict disease onset, susceptibility

Project: Research project

Description

Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center;it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 &3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods.
StatusFinished
Effective start/end date9/1/106/30/17

Funding

  • National Institutes of Health: $1,410,490.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $917,500.00
  • National Institutes of Health: $116,250.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,221,769.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,395,652.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,408,184.00
  • National Institutes of Health: $1,459,306.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $620,000.00
  • National Institutes of Health

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Parkinsonian Disorders
Synucleins
Parkinson Disease
Research
Molecular Biology
Progressive Supranuclear Palsy
Genes
Research Personnel
National Institute of Neurological Disorders and Stroke
Tauopathies
Pedigree
Brain
Subthalamic Nucleus
Lewy Bodies
Immunohistochemistry
Neurodegenerative Diseases
Genetic Association Studies
Informatics
Pathology
Social Responsibility

ASJC

  • Medicine(all)
  • Neuroscience(all)