Duchenne muscular dystrophy (DMD) is a deadly childhood disease that affects both skeletal and cardiac muscles and for which there is no effective treatment or cure. The majority of patients with DMD and those with a milder form of the disease, Becker muscular dystrophy (BMD) develop progressive cardiomyopathy that eventually leads to death in 20 and 50% of patients, respectively. We propose a mechanism of dystrophic cardiomyopathy disease progression that is dependent on signaling through the transcription factor nuclear factor-kappaB (NF-?B). Our previous work has demonstrated the requirement for NF-?B signaling in dystrophic skeletal muscles, however the implications of NF-?B signaling in dystrophic cardiac muscle remain unknown. In the proposed studies, Aim 1 will evaluate the relevance of NF-?B in dystrophic cardiomyopathy. Dystrophin- deficient mice (mdx) will be used as a model to determine how early NF-?B becomes activated, the specific NF-?B signaling pathway involved (classical vs. alternative), and the identity of cell types expressing NF-?B in dystrophic hearts. EMSA analysis, NF-?B reporter mice, immunostaining, western blotting, kinase assays, and FACS analysis will be used to evaluate Aim 1.
Aim 2 will determine the requirement for NF-?B signaling in disease development. Mdx mice deficient for NF-?B signaling in all cell types and specifically in cardiomyocytes will be evaluated for histological, functional, and gene expression differences compared to mdx mice without NF-?B ablation.
Aim 3 will investigate the mechanism by which NF-?B promotes dystrophic cardiomyopathy. Real time RT-PCR will be performed on cardiomyopathy-related genes that are known targets of NF-?B. Genes will be placed in functional groups (eg: fibrotic, inflammatory, survival) to determine if NF-?B is mechanistically promoting cardiomyopathy by targeting a specific group of genes. Additionally, a genome- wide search for all NF-?B targets will be performed using ChIP-sequencing to ensure an unbiased approach for evaluating NF-?B signaling targets is undertaken. The completion of these aims will provide significant insight into the role of the NF-?B signaling pathway in cardiomyopathy, as well as the relevance for targeting this signaling modulator for the treatment of DMD and BMD.

Public Health Relevance

The overall goal of this project is to understand how the protein nuclear factor-kappaB (NF-:?B) is contributing to heart disease in Duchenne and Becker muscular dystrophy. Understanding the role of NF-?B signaling in the heart is critical for determining if we can target this pathway for therapy to slow disease progression and improve quality of life for patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL099145-02
Application #
8209454
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$55,670
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210