2007 — 2011 |
Baloh, Robert Harris |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Mechanism of Peripheral Neuropathy From Mitofusin 2 Mutations @ Cedars-Sinai Medical Center
DESCRIPTION (provided by applicant): The candidate is an MD/PhD trained clinical neurologist with the career goal to investigate the mechanisms of neurodegeneration in peripheral neuropathies, using axonal Charcot-Marie-Tooth (CMT) as a prototypical disease. The career development plan will be jointly mentored by Dr. Alan Pestronk, a clinical expert in neuromuscular disorders, and Dr. Jeffrey Milbrandt whose lab focuses on molecular mechanisms of axonal degeneration and peripheral neuropathy - a unique merger allowing the candidate to become a successful independent investigator in this field. CMT neuropathies are among the most common inherited conditions of the nervous system, and currently are without treatment. They provide an opportunity for the clinician-scientist to understand the mechanisms of axonal degeneration in the peripheral nervous system, which likely will have broader implications for neurodegenerative disorders. Mitofusin 2 (MFN2) mutations are the most frequently identified cause of the axonal form of CMT (CMT2A), but the mechanism by which they lead to axonal degeneration is unknown. MFN2 is a mitochondrial membrane protein that is a critical component of the mitochondrial fusion apparatus, required for proper mitochondrial function. Our primary hypothesis is that MFN2 mutations lead to altered axonal mitochondrial transport and/or mitochondrial fusion, resulting in mitochondrial dysfunction, energy depletion and degeneration of distal peripheral axons. We will test this hypothesis by 1) introducing disease mutant forms of MFN2 seen in CMT2A patients into cultured sensory neurons, and examining their effect on axonal mitochondrial transport, mitochondrial fusion and oxidative function;and 2) generating a transgenic mouse model of CMT2A to study the detailed pathogenesis of the disease, corroborate our in vitro findings in an in vivo disease model, and to potentially provide a means of testing therapeutic agents for peripheral neuropathy and axonal degeneration in future studies. Relevance: Peripheral neuropathies, particularly those caused by metabolic disorders such as diabetes are a major cause of morbidity in the United States, yet the mechanisms of peripheral neuropathy remain poorly understood and there are no effective treatments. This proposal outlines research to understand the mechanism of an inherited form of peripheral neuropathy, in the hopes that this will provide insight, and eventually lead to effective treatments, for more commonly encountered types of neuropathy.
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2010 — 2014 |
Baloh, Robert Harris |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Defining the Mechanism of Tdp-43 Related Neurodegeneration
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle atrophy and spasticity due to degeneration of upper and lower motor neurons. Patients typically succumb to respiratory failure within 3-5 years of onset, with no effective therapies presently available. An important breakthrough in the understanding of ALS was recently provided by the (i) identification of pathologic aggregates of a protein called TDP43 in motor neurons from ALS patients, and (ii) the identification of dominantly inherited mutations in TDP43 in patients with familial ALS, solidifying the importance of TDP43 in the pathogenesis of ALS. TDP43 is a ubiquitiously expressed DNA/RNA binding protein capable of regulating transcription and alternative splicing, though its normal physiologic functions and role in ALS pathogenesis remain poorly understood. In our preliminary studies we have generated and characterized a mouse model which expresses a disease associated TDP43 mutant under the control of the mouse Prion promoter (Prp-TDP43A315T), and found that these mice develop a progressive and fatal neurodegenerative disease remarkably similar to ALS, recapitulating key aspects of the pathology including selective vulnerability of cortical layer 5 and spinal motor neurons. Based on these findings we propose that the molecular and cellular basis of selective vulnerability of cortical and spinal motor neurons in ALS are shared between mice and humans, and that misregulation of mRNA transcription or splicing by mutant TDP43 is a fundamental mechanism of disease in TDP43-related neurodegeneration. This proposal outlines experiments to refine our understanding of TDP43-related neurodegeneration. We propose to (1) characterize the phenotype of newly generated mouse lines expressing wild-type and disease mutant forms of TDP43;(2) define the relative contributions of neuronal and glial cells to neurodegeneration due to TDP43 mutations;and (3) identify transcriptional alterations and DNA/RNA targets of TDP43 in neurons selectively vulnerable to TDP43-induced neurodegeneration using a functional genomics approach. These studies will examine previously unexplored pathways of ALS pathogenesis, and identify new avenues for therapeutics development. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease, for which no effective treatments are available. We have developed a new mouse model of this disease, and are using it to better understand what causes nerve cells to degenerate in ALS, in order to design and test new treatments for the disease.
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