Pathogenesis of laminin-ot2-deficiency. Mutations in the human LAMA2 gene cause congenital muscular dystrophy, group 1 (CMD 1), a devastating, recessive disease of childhood. LAMA2 encodes laminin-c Beta 2, an extracellular protein that is abundant in skeletal muscle. The proposed experiments will test hypotheses about how loss of laminin-c_2 leads to the severe neuromuscular dysfunction in CMD1.
For Aims 1 & 2, we will examine the role of apoptosis in CMD1 pathogenesis. In culture, laminin-cz2-deficient myotubes are unstable and die by a process that is inhibited by the antiapoptosis protein Bcl-2. It is not known, however, whether apoptosis is important in the loss of CMD1 neuromuscular function in vivo. The proposed experiments willdetermine how disease in laminin-c_2-deficient mice is affected by targeted alterations of Bcl-2 family members.
For Aim 3, we will determine if muscle stem cell function is altered in CMD 1. Postnatal muscle contains multipotent stem cells, but no studies have examined these recently identified stem cells in diseased muscle. We will test the possibility that laminin- Beta 2-deficiency activates proliferation and alters the differentiation capability of these rare cells.
For Aim 4, we will determine if inappropriate re-entry into the cell cycle occurs in affected tissue. Inappropriate cell cycling can lead to death of normally post-mitotic cells including neurons and myofibers. We hypothesize that laminin-cz2-deficiency alters signal transmission resulting in dysregulation of the cell cycle. To test this hypothesis, we will determine if cell cycle regulators are inappropriately induced in laminin-c beta 2-deficient cells. The results will increase our understanding of CMD 1 pathogenesis and could suggest new routes to therapy, perhaps based on apoptosis inhibition, stem cell repair, or cell cycle inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR049496-01
Application #
6576703
Study Section
Special Emphasis Panel (ZAR1-TAS-B (O2))
Program Officer
Lymn, Richard W
Project Start
2002-09-19
Project End
2006-08-31
Budget Start
2002-09-19
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$296,382
Indirect Cost
Name
Boston Biomedical Research Institute
Department
Type
DUNS #
058893371
City
Watertown
State
MA
Country
United States
Zip Code
02472
Girgenrath, Mahasweta; Beermann, Mary Lou; Vishnudas, Vivek K et al. (2009) Pathology is alleviated by doxycycline in a laminin-alpha2-null model of congenital muscular dystrophy. Ann Neurol 65:47-56
Miller, Jeffrey B; Girgenrath, Mahasweta (2006) The role of apoptosis in neuromuscular diseases and prospects for anti-apoptosis therapy. Trends Mol Med 12:279-86
Girgenrath, Mahasweta; Weng, Shawn; Kostek, Christine A et al. (2006) TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J 25:5826-39
Girgenrath, Mahasweta; Kostek, Christine A; Miller, Jeffrey Boone (2005) Diseased muscles that lack dystrophin or laminin-alpha2 have altered compositions and proliferation of mononuclear cell populations. BMC Neurol 5:7
Nowak, Jonathan A; Malowitz, Jonathan; Girgenrath, Mahasweta et al. (2004) Immortalization of mouse myogenic cells can occur without loss of p16INK4a, p19ARF, or p53 and is accelerated by inactivation of Bax. BMC Cell Biol 5:1
Lykke-Andersen, Karin; Schaefer, Laura; Menon, Suchithra et al. (2003) Disruption of the COP9 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death. Mol Cell Biol 23:6790-7