Using Drosophila as our experimental system, we propose employing molecular genetic approaches to identify and characterize genetic modifiers of SMN, as such modifiers may define potential therapeutic targets for Spinal Muscular Atrophy (SMA). The available experimental reagents will allow us to probe tissue-specific (muscle vs. neuron) roles for SMN and its known modifiers at the Drosophila neuromuscular junction (NMJ), and to perform a high-throughput genetic screen to identify modulators of SMN activity using a novel SMN mutation and a unique collection of Drosophila mutations. In view of processes thought to be linked to SMN activity in the muscles and neurons, we propose to characterize functional modifiers of SMN specifically associated with the cytoskeleton and protein translation (Aim 1). In addition, we will further examine our initial observation that FGF signaling activity modifies NMJ abnormalities caused by loss of SMN function. This role will be evaluated in the context of a novel, SMN dependent, muscle deterioration phenotype we uncovered (Aim 2). Finally, we will extend our genetic screens for SMN modifiers using hypomorphic SMN alleles, which provide an improved SMA model and will also use behavioural assays to evaluate the activity of specific adult motorneurons (Aim 3). Our studies will be evaluated in light of a hitherto unprecedented characterization of the Drosophila NMJ (Van Vactor laboratory) while our other collaborative efforts, will permit us to validate results across species in C. elegans (Hart laboratory) and mammalian cells (Rubin laboratory).

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01NS066888-05
Application #
8704293
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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