The candidate is a clinical neurologist (MD) with a career goal of investigating the genetic and molecular basis of human neuromuscular diseases, focusing primarily on amyotrophic lateral sclerosis (ALS). The candidate has significant prior laboratory experience, with a track record of successful research projects in neuropharmacology, neurodevelopment, and most recently, neurogenetics. In order to further prepare for successful independent research, the candidate's career development plan includes graduate-level courses in biostatistics, bioinformatics, and genomics, as well as seminars and intensive courses on next-generation sequencing and related methods. The proposed development plan and scientific training will take place at Washington University in St. Louis, an institution with particular strengths in both genetics/genomics and the study of ALS. The neurogenetics community is robust and will provide the candidate with important intellectual assistance and collaborations. The scientific training will be jointly mentored by Dr. Alison Goate, whose lab focuses on the genetics of dementia and addiction, and Dr. Robert Baloh, whose lab studies the molecular basis of neurodegeneration in ALS using tissue culture and animal models. Dr. Goate's expertise in human genetics and sequencing methods coupled with Dr. Baloh's experience in modeling human neuromuscular diseases will provide the candidate with the set of research tools needed to succeed as an independent investigator studying the genetic and molecular basis of neurologic diseases. The candidate's research proposal aims to identify novel genes causing ALS, an untreatable neurodegenerative disease producing loss of motor neurons, progressive paralysis, and death from respiratory failure. Although the majority of ALS cases are sporadic, the genes responsible in familial cases have provided important insights into all forms of the disease. However, known ALS genes still only explain 25% of familial cases. To identify additional familial ALS disease genes, the candidate will: 1) Screen a large cohort of familial and sporadic ALS patients for mutations in known ALS genes. This screen will be performed using pooled-sample sequencing, an innovative method made possible by next-generation sequencing capabilities pioneered by one of our key collaborators. Novel disease-causing mutations will be followed up with phenotypic analysis. This screen will also identify a cohort of ALS families without mutations in any known ALS disease gene to be studied with whole-exome sequencing. 2) Familial cases of ALS without mutations in known genes will then undergo whole-exome analysis, a next- generation sequencing method that allows all coding regions in the human genome to be sequenced simultaneously for variations. To narrow the number of candidate pathogenic mutations, a host of bioinformatic techniques will be used. Candidate ALS genes identified will then be screened for additional mutations in other ALS patients using the same pooled-sample sequencing strategy as in (1). The identification of novel ALS disease genes will pave the way for future studies aimed at understanding the molecular mechanism by which these mutations lead to neurodegeneration, using tissue culture and animal modeling. This work will provide key insight into the molecular basis of ALS and will immediately impact efforts aimed at therapeutic development for this untreatable disease.
Amyotrophic lateral sclerosis (a.k.a. Lou Gehrig's disease) is an untreatable disease characterized by progressive paralysis and eventual death. Identification of genes responsible for hereditary forms of ALS will shed light on why the disease occurs and guide how therapies might be developed. This project uses state-of- the-art genetic sequencing technologies to uncover these genes.
|Albulym, Obaid M; Kennerson, Marina L; Harms, Matthew B et al. (2016) MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Ann Neurol 79:419-27|
|Strickland, Alleene V; Schabhüttl, Maria; Offenbacher, Hans et al. (2015) Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1. J Neurol 262:2124-34|
|Cirulli, Elizabeth T; Lasseigne, Brittany N; Petrovski, Slavé et al. (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436-41|
|Cady, Janet; Allred, Peggy; Bali, Taha et al. (2015) Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol 77:100-13|
|Scoto, Mariacristina; Rossor, Alexander M; Harms, Matthew B et al. (2015) Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology 84:668-79|
|Weihl, Conrad C; Baloh, Robert H; Lee, Youjin et al. (2015) Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord 25:289-96|
|Weihl, Conrad C; Iyadurai, Stanley; Baloh, Robert H et al. (2015) Autophagic vacuolar pathology in desminopathies. Neuromuscul Disord 25:199-206|
|Liu, Qing; Waltz, Shannon; Woodruff, Grace et al. (2014) Effect of potent ?-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 71:1481-9|
|Cady, Janet; Koval, Erica D; Benitez, Bruno A et al. (2014) TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol 71:449-53|
|Johnson, Janel O; Pioro, Erik P; Boehringer, Ashley et al. (2014) Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 17:664-666|
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