Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

Information

  • Research Project
  • 7646786
  • ApplicationId
    7646786
  • Core Project Number
    R15AR055360
  • Full Project Number
    1R15AR055360-01A2
  • Serial Number
    55360
  • FOA Number
    PA-06-042
  • Sub Project Id
  • Project Start Date
    4/3/2009 - 15 years ago
  • Project End Date
    8/31/2011 - 13 years ago
  • Program Officer Name
    NUCKOLLS, GLEN H.
  • Budget Start Date
    4/3/2009 - 15 years ago
  • Budget End Date
    8/31/2011 - 13 years ago
  • Fiscal Year
    2009
  • Support Year
    1
  • Suffix
    A2
  • Award Notice Date
    4/3/2009 - 15 years ago

Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

DESCRIPTION (provided by applicant): Recent evidence obtained in this laboratory indicates that treatments which reduce the nuclear activation of the transcription factor nuclear factor-kappaB (NFkB) have distinct beneficial effects in substantially reducing the loss of striated muscle fibers and restoring the resting membrane potential in severely dystrophic (mdx) muscle fibers [2]. These results indicate a clear need for investigating the potential clinical utility of NFkB inhibitors in treating Duchenne and Becker muscular dystrophies. The purpose of these proposed studies is to determine the clinical utility of ursodeoxycholic acid (UDCA) which preliminary studies show inhibits the NFkB pathway and improves whole body tension (WBT) development in the mdx mouse. Preliminary studies showing an increased total cellular expression of p65 in dystrophic (mdx) muscle also indicate the potential clinical utility of agents that decrease the expression of p65 by interfering with the Sp1 signaling pathway. Therefore, the drug gossypol (Gp) will be investigated in preclinical trials using the mdx mouse. These two drugs inhibit the nuclear binding and transactivation of NFkB (UDCA) and the total cellular expression of p65 (Gp). UDCA is clinically used to treat inflammatory bowel disorders and Gp had been used in human populations as a male anti-sterility agent. Undergraduate, graduate, and osteopathic medical (D.O.) students (Truman State University, A.T. Still University) will be involved in assessing the effects of these agents on tension development in two isolated mdx muscles (gastrocnemius, costal diaphragm) and on whole body strength in intact mdx mice. This study is done in parallel with translational investigations that include assessments of cytosolic and nuclear levels of NFkB in chronically treated mdx muscle, the expression of inflammatory cytokines in plasma and muscle extracts, resting membrane potential, plasma creatine kinase levels, skeletal muscle fibrosis, and histological determinations of the total number of fibers, the proportion of striated vs necrotic fibers, percent centro-nucleation, and the distribution of fiber diameter and cross sectional areas in dystrophic mdx muscle. The proposed studies will test the specific hypothesis that these specific inhibitors improve limb and respiratory muscle function in the mdx mouse and will provide essential pre-clinical information that can be used in clinical trials for patients with Duchenne and Becker muscular dystrophies. PUBLIC HEALTH RELEVANCE: These studies will examine the potential therapeutic efficacy of ursodeoxycholic acid and gossypol which are members of a class of drugs (NFkB inhibitors) that have recently been shown to have beneficial effects in the mdx mouse, a model for Duchenne muscular dystrophy. The results of the proposed investigations will provide critical information for establishing clinical trials to test drug efficacy in patients with Duchenne and Becker muscular dystrophy.

IC Name
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
  • Activity
    R15
  • Administering IC
    AR
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    167169
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    846
  • Ed Inst. Type
    SCHOOLS OF OSTEOPATHIC MEDICINE
  • Funding ICs
    NIAMS:167169\
  • Funding Mechanism
    Research Projects
  • Study Section
    SMEP
  • Study Section Name
    Skeletal Muscle Biology and Exercise Physiology Study Section
  • Organization Name
    A.T. STILL UNIVERSITY OF HEALTH SCIENCES
  • Organization Department
    PHYSIOLOGY
  • Organization DUNS
    006323315
  • Organization City
    KIRKSVILLE
  • Organization State
    MO
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    63501
  • Organization District
    UNITED STATES