The lack of repair within the human central nervous system remains one of the most intractable problems confronting biomedicine. Transplantation studies have shown that adult neurons can regrow substantial distances if supplied with tissue from regions of embryonic central (CNS) and peripheral (PNS) nervous system or from adult PNS, but not from adult CNS. Moreover, acellular grafts containing extracellular matrix (ECM) components can also support some regrowth. These studies emphasize that the lack of repair in the adult CNS is due to the absence of the appropriate environment for growth rather than an inherent deficit of CNS neurons. A cellular and molecular approach is proposed here to characterize one neuronal receptor system that can support neurite outgrowth during development and regeneration. One prominent component of the acellular environment is laminin (LN), a potent stimulator of neuronal process outgrowth from CNS and PNS neurons. LN is abundantly expressed in developing CNS and PNS fiber tracts yet in the adult is only present in the PNS. This grant proposal is focused on one of the major receptor systems for LN expressed on the surface of neuronal growth cones - integrins - and in particular on one experimentally advantageous member of this gene family: the integrin alpha1/beta1, a LN receptor. The experiments proposed here are designed to elucidate (i) the structural determinants by which the alpha1/beta1 integrin binds to extracellular matrix ligands, with particular focus on how in different cell types this integrin binds to a different repertoire of ligands; and (ii) how this receptor and associated proteins function during growth cone extension in defined environments in vitro. A combination of molecular, biochemical, immunological, cell culture, and video microscopy techniques will be used to determine the function of alpha1/beta1 integrins in promoting and sustaining nerve growth. Defining the molecular determinants of nerve growth and repair may help in creating a permissive environment for the growth of adult neurons in clinical paradigms of repair, as well as slowing the progress of neurodegenerative disease.
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