Astrocytes are essential for neuronal survival and function. Yet every neurodegenerative disease and every injury to the brain and spinal cord results in "activation" and proliferation of astrocytes, a process termed astrocytosis, which adversely affects neuronal survival and function. Thus, the astrocyte is a two-edged sword, supporting homeostasis in health, but, in pathologic conditions, their activation results in neuronal loss. As an example, the scar that forms in the weeks following stroke is caused by astrocyte proliferation, which further damages neurons, preventing recovery and increasing disability. In chronic neurological diseases, such as Multiple Sclerosis, there is a progressive astrocytosis and a corresponding progressive loss of neurons. GliaMed, Inc., a biotechnology company dedicated to using our proprietary, patent-protected technology to treat a range of neurodegenerative diseases and astrocytoma, has taken the approach that understanding The molecular mechanisms of homeostasis will, by definition, identify important and novel therapies. With this as its scientific cornerstone, and supported by more than a decade of federal and foundation research grants awarded to the Company's scientific founder, the PI on this application, GliaMed has identified both cellular and molecular targets for the effective treatment of a range of conditions that result in loss of CNS homeostasis. In specific, we demonstrated a number of years ago that astrocytes, one of the major celt types in the CNS, are sustained out of the cell cycle by contact with a protein component specific to the neuronal cell-surface. We have recently identified the astrocyte-expressed receptor, termed GMg, and its neuronal ligand, NrS1, that mediate both forward and reverse signaling between these cell types, that results in a number of biologies, including astrocyte cell-cycle arrest. In this application, we provide data elucidating aspects of these interactions, and describe our lead compounds. Further, we provide evidence that these compounds which are based on GM9-NrS1 binding, rescue neurons from programmed cell death and promote axogenesis, both in vitro and in vivo. The overall Specific Aim of this application, based on Preliminary Data provided herein, is to optimize these compounds for in vivo stability and saturation of target sites within the CNS. These data will support the transition of the GliaMed lead compounds from preclinical to clinical development.
Thesaurus Terms: astrocyte, biological signal transduction, cell cell interaction, drug design /synthesis /production, nerve /myelin protein, neural degeneration, neuropharmacologic agent biotherapeutic agent, cell proliferation, peptide laboratory mouse, laboratory rat, peptide chemical synthesis
