PROJECT SUMMARYCongenital and acquired bone diseases constitute a major public health issue. Research conducted in the lastdecades has led to improved preventive and therapeutic interventions, but the diseases continue today tocause disability, morbidity and mortality at a high rate. More research is therefore needed to further decipherdisease mechanisms and develop better interventions. This project is designed to contribute to this effort byincreasing current knowledge of the molecular regulation of skeletal stem cells (SSCs) and their osteoblasticdescendants. We will test the hypothesis that SOXC transcription factors critically control bone formation fromdevelopment onwards by directing SSCs and pre-osteoblasts to express a wide array of genes that ensuretheir self-renewal and inhibit their osteoblastic differentiation. This hypothesis is supported by preliminaryevidence that the SOXC genes, i.e., Sox4, Sox11, and Sox12, are actively expressed in SSCs and earlyosteoblastic cells in the mouse, and that both their specific co-inactivation and the overexpression of SOX11 inSSCs result in underdeveloped bone in embryos and in low bone mass in adult mice. This hypothesis is alsosupported by published evidence that SOX4 is a candidate gene for osteoporosis and low bone mass inhumans and that SOX11 heterozygous mutations cause characteristic dysmorphic features. Two specific aimsare proposed to test this hypothesis. Aim 1 is to use SOXC loss-of-function and gain-of-function mouse modelsto definitively assess the importance of SOXC genes in osteogenesis throughout life. Aim 2 is to use cutting-edge molecular and functional approaches to identify the transcriptional targets of SOXC proteins in SSCs andpre-osteoblasts, and the importance of these targets in mediating the roles of SOXC proteins in these cells.Altogether, it is expected that new knowledge acquired upon completion of this project will significantly deepencurrent understanding of SSC and skeleton regulation from development to late adulthood and will therebyspark novel ideas and provide new means to better understand and treat bone diseases.
|Effective start/end date||7/21/16 → 6/30/21|
- National Institutes of Health: $455,695.00
SOXC Transcription Factors
Bone and Bones