Projects and Grants per year
Grants and Contracts Details
Description
In this supplemental project, we seek to capitalize on a confluence of exciting new data, innovative
technology, and the unique expertise of three new collaborators. Data from our parent project have identified
an obscure sphingomyelinase isoform -- neutral sphingomyelinase-3 (nSMase-3) -- as a potential mediator of
diaphragm weakness stimulated by TNF or severe heart failure. We propose to test this thesis by a
multidisciplinary strategy. The experimental approach includes cell culture systems, a newly-created
transgenic mouse line, and diaphragm biopsies from humans with heart failure. The project is made possible
by a powerful team of three new collaborators who are experts in molecular biology, transplantation surgery,
and human genetics. The goal of our proiect is to evaluate nSMase-3 as a potential mediator of diaphragm
weakness in heart failure and a target for future therapeutic development. We have two specific aims:
Aim 1. To evaluate nsMase-3 as a mediator of TNF-induced oxidant activity and weakness. Experiment
jJ will test the hypothesis that nsMase-3 is constitutively expressed by murine skeletal muscle and is
upregulated by TNF. Experiment 1.2 will test the hypothesis that muscle-specific nSMase-3 deficiency will
abolish TNF effects on diaphragm oxidant activity and specific force. Aim 2. To test for associations
between nsMase-3 and cardiovascular disease in humans. Experiment 2.1 will test the hypothesis that
nSMase-3 mRNA, nSMase-3 protein, and SMase activity are elevated in diaphragm and pectoralis muscles of
patients undergoing surgery for heart failure. Experiment 2.2 will test the hypothesis that single nucleotide
polymorphisms (SNPs) in the Smpd4 gene that codes for nsMase-3 will modulate expression or splicing of
the gene in human tissue.
Status | Finished |
---|---|
Effective start/end date | 4/1/08 → 2/28/15 |
Funding
- National Institute Arthritis Musculoskeletal & Skin
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Projects
- 1 Finished
-
Respiratory Muscle Weakness in Chronic Inflammation
Andrade, F. (PI), Stevenson, J. (CoI) & Reid, M. (Former PI)
National Institute Arthritis Musculoskeletal & Skin
4/1/09 → 2/28/15
Project: Research project