We hypothesize that within the intervertebral disc (IVD), a niche exists comprising the nucleus pulposus and the inner layer of the annulus fibrosus and the cartilage endplate. In the niche, two events govern successful maintenance of disc cell function: the ability of progenitor cells to provide replacement cells, and the power of this cell population for renewal. In the disc niche, environmental conditions are unique in that the progenitor cells experience a low oxygen tension and possibly a low pH.
Cellular adaptation to low oxygen (hypoxia) is an important biological problem not only in relation to pathological conditions such as cancer and ischemic diseases, but also in normal foetal development and in cell differentiation.
The overall goal of this project is to investigate the role of hypoxia and HIFs transcription factors and the molecular mechanisms that are involved in the biology of IVD, especially in proliferation, survival, differentiation of NP cells and formation of NP tissue, in both developmental and degenerative processes.
To achieve this aim, the proposed research activities will focus on: mice models of gene invalidation particularly regarding the HIF pathway (HIF-1α, HIF-2α and Von Hippel Lindau tumor suppressor protein). To specifically inactive these genes during embryonic development, growth or aging, conditional and inducible KO will be generated using Cre or Cre-ERT2 strategies and promoters for Foxa2 (notochordal cells) or aggrecan (NP cells).
The expected results are to improve our understanding of IVD development, aging and associated pathologies. Such advances in the comprehension of IVD physiopathology may lead to the development of advanced approaches by defining novel therapeutic targets and/or innovative cell-based tissue engineering strategies.
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