This proposal describes a 5 year plan for mentored clinical and laboratory training designed to prepare the candidate to an independent academic career as a physician-scientist. The applicant is an MD, PhD, who recently completed the 4 year residency program in Medical Genetics at Baylor College of Medicine. The career development plan includes mentored research training which will include: i) regular meetings with the mentor, ii) biannual meetings with a Scientific Advisory Committee iii) didactic courses, iv) seminars, v) lab meetings, vi) national meetings, and vii) international meetings. The training will take place at Baylor College of Medicine providing an excellent training environment with access to the latest tools of genome study. The project main aim is to elucidate the biology of the human peripheral nerve in health and disease through the identification of novel genes implicated in Charcot-Marie-Tooth (CMT) disease. CMT is a progressive neurological disease caused by deterioration of the peripheral nerves with secondary muscle wasting and weakness. The disease is extremely heterogeneous both clinically and molecularly. We will study a cohort of well described patients with hereditary peripheral neuropathy and no obvious disease-causing sequence variants in any of the 32 known CMT genes. The genomic profile, including copy number variations and single nucleotide variations will be determined for index patients with the application of state of the art molecular techniques (next generation sequencing and genomic microarrays). Genomic data, after bioinformatics processing and filtering, will be mined to identify candidate genes. The methods of conventional genetics, molecular biology, and bioinformatics will be implemented to further validate the disease-causing potential of novel candidates

Public Health Relevance

The project main aim is to elucidate the biology of the human peripheral nerve in health and disease through the identification of novel genes implicated in Charcot-Marie-Tooth disease (CMT). This proposal focuses on using state of the art genome sequencing, and array comparative genomic hybridization to systematically assess genetic variants in selected patients with CMT neuropathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23NS078056-01A1
Application #
8441903
Study Section
NST-2 Subcommittee (NST)
Program Officer
Gwinn, Katrina
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$156,600
Indirect Cost
$11,600
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Pehlivan, Davut; Beck, Christine R; Okamoto, Yuji et al. (2016) The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. Genet Med 18:443-51
Lodder, Elisabeth M; De Nittis, Pasquelena; Koopman, Charlotte D et al. (2016) GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. Am J Hum Genet 99:704-710
Nguyen, Thy P; Biliciler, Suur; Wiszniewski, Wojciech et al. (2015) Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease. J Clin Neuromuscul Dis 17:69-71
Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz et al. (2015) Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep 12:1169-83
Watkin, Levi B; Jessen, Birthe; Wiszniewski, Wojciech et al. (2015) COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet 47:654-60
Karaca, Ender; Harel, Tamar; Pehlivan, Davut et al. (2015) Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron 88:499-513

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