LELAND STANFORD JUNIOR UNIVERSITY, THE
Grant: $302,821 - National Institutes of Health - Sep. 30, 2009
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Award Description: The objective of our project is to identify genotype-phenotype associations in individuals affected by hereditary optic nerve disorders through integrative systems-biology based approaches and the application of cost-efficient sequencing technologies. We are currently in year 3 of this grant proposal and the specific aims (AIM 1-3) of this grant have not been modified. As described in this supplement, we have developed and validated novel genome technologies for multiplex target amplification and high-accuracy array-based medical resequencing (MRS). Our integrated sample preparation and DNA sequencing pipeline now allows for sequence analysis of more than 500 genes in each individual within 24 hours. In the next stage of this project we transition from the successful genome technology development to high-throughput experimentation, DNA sequencing and data analysis. During this transition period we will require additional personnel support for laboratory work and computational data analysis as well as upgrades to our equipment. We have already interviewed and identified two new candidates who are qualified for these jobs (see budget justification). The activities proposed in this administrative supplement will accelerate the pace and achievement of our research and promote job creation and can be accomplished within the current competitive segment (year 4 of our project).
Project Description: A key goal of the National Plan for Eye and Vision Research is to determine the basic biology and underlying pathogenesis of glaucoma and optic neuropathies, which affect more than 2.2 million Americans. This goal will require understanding the neurodegenerative process, including the insults that initiate retinal ganglion cell death, and mediate end-stage optic nerve damage. Mitochondria play a central role in energy metabolism of nerve cells and related clinical disorders. The objective of our project is to identify genotype-phenotype associations in individuals affected by hereditary optic nerve disorders through integrative systems-biology based approaches and the application of cost-efficient sequencing technologies. Specifically, we will identify DNA variations in 600 nuclear genes involved in mitochondrial functions in hundreds of individuals diagnosed with Leber's Hereditary Optic Neuropathy (LHON), a degenerative optic nerve disease leading to blindness. LHON is primarily maternally inherited (mtDNA) and exhibits highly variable penetrance suggesting synergistic effects with nuclear-encoded mitochondrial components. Indeed, we have already identified 34 mitochondrial proteins associated with hereditary optic neuropathies. Here we request a Recovery Act Administrative Supplement for our active parent grant in order to support the transition of our project from the phase of genome technology development to high-throughput data generation and analysis. The activities proposed in this administrative supplement will accelerate the pace and achievement of our research and promote job creation and can be accomplished within the current competitive segment (year 4 of our project). Our high-accuracy array-based resequencing pipeline currently achieves a false positive rate of approximately 1 in 50,000 bp with false negatives close to 0 for more than 95% of all targeted sequences. The correlation of the identified genetic variations (incl. rare alleles with <0.05% MA
Jobs Summary: No jobs retained or created yet. (Total jobs reported: 0)
Project Status: Not Started
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