The long-term goal of this project is to understand the principles by which cell-cell signaling factors control vertebrate development. The investigator's focus is on receptor tyrosine kinases, receptor tyrosine phosphatases, and their ligands, a set of molecules known to have important roles in development, physiology and disease. The Eph receptors are the largest known subfamily of receptor tyrosine kinases, with more than 12 members. Remarkably, all were initially identified as orphan receptors without known ligands, and their specific functions were unknown. Recently, the first members of a corresponding Eph ligand family were identified, opening the way for new studies into function. Novel roles in neural development have already been identified, particularly in axon guidance. The main goal of this proposal is to further characterize functions of the Eph family in neural development. The investigator will focus on roles in axon guidance, but also plans to study related developmental processes such as guidance of cell migration. His studies will involve a combination of molecular-genetic, cellular and embryological approaches, including: 1) characterization of in situ expression and binding patterns of Eph ligands and receptors in embryos, 2) effects of Eph ligands and receptors on assays of cell behavior, in vitro and in vivo, and 3) molecular interactions and signaling properties of Eph receptors and ligands. PTP-NP is a new receptor-type protein tyrosine phosphatase, and is notable as a particularly early and specific marker for developing pancreatic endocrine cells. Despite the medical importance of these cells, no pancreas-specific extracellular control factors have been found. Using a soluble version of the receptor, a candidate ligand for PTP-NP has been identified, which could be a regulator of pancreatic endocrine cells. The investigator's aim is to clone the ligand, and to further characterize the biology of this ligand-receptor system. The investigator expects his work on the basic biology of developmental control could help to understand abnormalities that lead to disease. Because the focus is on the identification and characterization of novel molecules that control cell behavior, the work could lead to the development of new therapeutic agents. For the Eph family, potential applications could be in the repair of damage to neural connections in the brain and spinal cord. For PTP-NP, applications could be in the growth or regeneration of pancreatic endocrine cells to treat diabetes.
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