The proposed research is a continuation of our ongoing studies of mechanisms mediating glial lineage commitment and glial responses to injury. Bone morphogenetic protein (BMP) signaling promotes astrocytic and inhibits oligodendroglial lineage commitment both in vitro and in vivo. BMPs exert their biological effects by binding to type I (BMPRIa and BMPRIb) and type II (BMPRII) receptor subunits that are organized with minor modifications of the prototypical TGFbeta subclass. This proposal will examine the role of different BMPR subunits in astroglial lineage commitment and glial responses to injury, and will define molecular mechanisms underlying effects of BMP signaling on gliogenesis. Glial lineage commitment is also influenced by factors that inhibit astrogliogenesis. Beta-1 integrin signaling inhibits astrocytic lineage commitment and is able to suppress the stimulatory effects of BMP signaling. Further, activation of beta-1 integrin signaling inhibits glial hyperplasia after spinal cord injury without altering astrocytic hypertrophy. This proposal will also examine the mechanisms underlying these effects of beta-1 integrin signaling and how they modulate the effects of BMP signaling. The first specific aim will define mechanisms mediating the effects of BMP signaling on glial responses to spinal cord injury. This part of the proposal will utilize conditional null mutation of BMP receptor subunits from different populations of precursor cells and astrocytes to define the roles of different BMPR subunits in glial lineage commitment and injury responses. The second specific aim will examine the effects of conditional null mutation of beta-1 integrin or enhancement of beta-1 integrin signaling on glial lineage commitment and glial responses to spinal cord injury. A specific focus will be on mechanisms by which beta-1 integrin and BMP signaling interact and identification of the genes that are activated in response to the two signaling pathways. It is hoped that these studies will indicate biochemical loci where therapeutic intervention in disease processes may lead to a return to normal neurological function. More specifically, understanding the factors that regulate gliogenesis in the adult spinal cord may lead to therapies designed to facilitate regeneration and restoration of function.
After injury to the nervous system, increased numbers of cells called astrocytes accumulate at the site of the injury. These cells mediate important functions for the repair of damage to the spinal cord or brain, but they eventually lead to formation of a scar that hinders regeneration. The proposed studies will examine what controls the formation of such a scar after spinal cord injury and seek to define ways of preserving the beneficial effects of astrocytes while limiting the detrimental effects.
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