Disturbances in RNA metabolism have emerged as an important contributor to several related neurological diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myopathy (IBM). The familial and sporadic forms of these degenerative diseases are typically characterized pathologically by cytoplasmic inclusions composed of fibrillar deposits of RNA-binding proteins (RBPs). Moreover, mutations in RBPs or other proteins that regulate RNA metabolism frequently cause the familial forms of these diseases. Over the past 7 years my lab has been at the forefront of illuminating the molecular basis for these diseases, including identifying new diseases genes, elucidating the normal function of these and other disease-related genes, and determining the consequences of disease mutations. Based on these studies we have advanced the hypothesis that disturbance in the assembly, disassembly and function of diverse RNA-protein assemblies, including cytoplasmic RNA granules, underlies the pathogenesis of the aforementioned neurological diseases. We have developed a comprehensive research program that, over the next 8 years, will investigate the molecular bases of RNA granule assembly, elucidate in detail how RNA granule dynamics are regulated, determine the role of RNA granules in spatial and temporal control of gene expression, and most importantly elucidate the mechanism whereby defects in RNA granule dynamics contribute to neurological diseases.

Public Health Relevance

Disturbances in the assembly and disassembly of RNA granules has recently emerged as the key defect underlying common neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). This project seeks to understand the molecular basis of RNA granule assembly and how this process is disturbed in disease. These insights will be used to guide therapeutic intervention for ALS and related degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097974-05
Application #
10063575
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Gubitz, Amelie
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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