Deterioration of the intervertebral disks, located between each vertebra, is common in older vertebrates. Age-related changes in the intervertebral disks are thought to cause most cases of back pain. Back pain affects nearly everyone at some point of their lives, with 1.5 million people a year becoming disabled. The center region of the intervertebral disk is composed of soft, highly hydrated tissue called the nucleus pulposus. Dehydration or damage to the nucleus pulposus can result in inefficient transfer of load between the intervertebral disks, leading to disk herniation and other types of disk disease. There are no cures for disk damage/degeneration. Both the hedgehog and Bmp signaling pathways have been implicated in the formation and postnatal maintenance of a number of tissues, however the tools necessary to investigate the function of these important signaling pathways in the intervertebral disks have not been available. In this proposal, we will use novel mouse stains and techniques we have recently developed to test our hypothesis that alterations in hedgehog and Bmp signaling pathways are responsible for age-related disk degeneration.
In Aim 1, the role of hedgehog signaling in the development and maintenance of the intervertebral disks will be examined.
Aim 2 will investigate the role a specific hedgehog family member, Shh, plays in the postembryonic maintenance of healthy intervertebral disks.
In Aim 3, we propose to remove combinations of Bmp proteins, which function downstream of hedgehog signaling, from the intervertebral disks to investigate our hypothesis that inadequate stimulation of intervertebral disk cells by Bmp proteins results in disk degeneration. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG029353-01A1
Application #
7316278
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Williams, John
Project Start
2007-09-01
Project End
2012-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$295,518
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Maier, Jennifer A; Lo, YinTing; Harfe, Brian D (2013) Foxa1 and Foxa2 are required for formation of the intervertebral discs. PLoS One 8:e55528
Martin, John T; Gorth, Deborah J; Beattie, Elizabeth E et al. (2013) Needle puncture injury causes acute and long-term mechanical deficiency in a mouse model of intervertebral disc degeneration. J Orthop Res 31:1276-82
Bruggeman, Bradley J; Maier, Jennifer A; Mohiuddin, Yasmin S et al. (2012) Avian intervertebral disc arises from rostral sclerotome and lacks a nucleus pulposus: implications for evolution of the vertebrate disc. Dev Dyn 241:675-83
Choi, Kyung-Suk; Lee, Chanmi; Harfe, Brian D (2012) Sonic hedgehog in the notochord is sufficient for patterning of the intervertebral discs. Mech Dev 129:255-62
Choi, Kyung-Suk; Harfe, Brian D (2011) Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs. Proc Natl Acad Sci U S A 108:9484-9
Maier, Jennifer A; Harfe, Brian D (2011) Nuclei pulposi formation from the embryonic notochord occurs normally in GDF-5-deficient mice. Spine (Phila Pa 1976) 36:E1555-61
Smith, Lachlan J; Nerurkar, Nandan L; Choi, Kyung-Suk et al. (2011) Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech 4:31-41
Choi, Kyung-Suk; Cohn, Martin J; Harfe, Brian D (2008) Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Dev Dyn 237:3953-8