I. Mechanisms of neurotrophin signaling through the p75 receptor: Our lab studies the signaling mechanisms regulating neuronal survival. Programmed cell death in the nervous system is a naturally occurring process in mammalian development; however, abnormal apoptosis is the basis for many neuropathologies, e.g. Alzheimer''s and Parkinson''s disease and ischemic injury. The delicate balance between neuronal survival and death is regulated, in part, by a family of growth factors referred to as the neurotrophins. The target tissues to which the neurons project produce members of this family of trophic factors. The neurotrophins promote neuronal survival and differentiation through binding to the Trks, a family of tyrosine kinase receptors, and induce apoptosis through a 75kD receptor, p75. While significant progress has been made in elucidating the mechanisms by which the Trks promote survival, much less is known about how p75 induces cell death. We recently discovered that pro-death ligands promote p75 cleavage by γsecretase, which releases a transcription factor, NRIF, to enter the nucleus. This process is required for the receptor''s apoptotic signal.This research will reveal the mechanisms underlying normal mammalian neural development and function. Moreover, understanding the regulation of neural cell survival is essential for developing therapeutic strategies for neuropathologies involving apoptosis, which include many diseases and nerve lesions.
II. Process by which apoptotic neurons are phagocytosed: Following the extensive apoptosis that occurs during development of the nervous system, the resulting neuronal corpses must be efficiently removed to prevent an inflammatory response, which can eventually lead to autoimmunity. Unfortunately, the molecular mechanisms underlying this phagocytic process in the nervous system are poorly understood. We recently demonstrated that satellite glial precursor cells are the primary phagocytes that engulf the many neuronal corpses in the developing dorsal root ganglia (DRG) and identified a novel engulfment receptor, Jedi1, as mediating the engulfment by glial precursors. Current efforts are aimed at determining the mechanisms by which Jedi1 signals engulfment and investigating its role in regulating phagocytosis in other regions of the developing nervous system.
III. Molecular mechanisms of myelin formation: The other area of research in the lab is to elucidate the mechanism by which myelin forms. Myelin is a multilamellar structure that ensheaths axons and allows for the rapid conduction of electrical signals, acts as a protective barrier for axons, regulates regeneration and provides trophic support for neurons. This structure is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the CNS. The formation of peripheral myelin during development is initiated by yet to be identified signals from the axon with which the Schwann cells are associated. The overall objective of this project is to elucidate the mechanisms regulating the formation of this essential neural structure. We found that activation of the transcription factor NF-ΚB in Schwann cells is a critical factor for their differentiation into a myelinating phenotype and are currently investigating the role of NFkB in the normal differentiation process and in models of demyelinating neuropathies.
Postdoctoral Positions Available
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