Research Project
10216278
Injury to the central nervous system (CNS) by disease or trauma causes a cascade of cellular responses that must occur to restore the delicate microenvironment necessary for function of the CNS. However, the changes caused to CNS tissue by these cellular responses may create an environment that is not permissive to functional regeneration. For patients, this results in permanent loss or aberration of function. In the case of spinal cord injury (SCI), patients often develop allodynia and other pain syndromes in addition to motor impairment. We are seeking to gain a better understanding of the cellular processes that occur following SCI that cause impairment and to develop therapies of small molecules and optogenetically responsive cells to promote functional repair of neural circuits. We are specifically interested in the changes that occur in activated astrocytes and the alterations in the expression of glycans following SCI that occur during gliosis. We will develop a model of reactive astrogliosis using precursor derived astrocytes that can be used to delineate the signaling mechanisms responsible for astrogliosis. We hypothesize that extensive changes in glycosylation occur during astrogliosis that mediate the injury response after SCI and will test this by characterizing large scale changes in glycosylation after SCI. Glycomics is an advancing field and this would be the first study documenting the changes in glycosylation in the CNS after an injury. Our second and third aims are more translational in nature and will develop therapeutics that both mitigate inhibitory signals after SCI and provide positive cues to stimulate regeneration. Chondroitin sulfate (ChS) is a glycan known to inhibit regeneration and we hypothesize that compounds can be identified that bind to and mask ChS from inhibitory receptors. To provide positive stimuli, we will develop and test an optogenetic system that we hypothesize can be used to control the behavior of cells (proliferation, gene expression etc) post-implantation by non-invasive means.
