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Contenu archivé le 2024-06-10

Molecular and cellular studies of a novel family of regeneration and injury associated neuronal signalling molecules

Objectif



The inability of neurons of the mammalian central nervous system (CNS) to regenerate following injury is the cause of much morbidity and mortality in humans. Motor neurons are the exception to this and are the only adult mammalian central neurons to regenerate following injury. This regenerative ability is dependent on the environment of the peripheral nerve and an intrinsic capacity of motor neurons for regrowth. A thorough understanding of the process by which these central neurons regenerate in a peripheral nerve environment will have profound implications for attempts to repair the human CNS. However, little is currently known of the neuron-glia and neuron-target signals which underlie the regeneration of the adult mammalian peripheral nervous system. Members of this partnership have recently identified a novel motor neuron-produced secreted protein, Reg-2, and demonstrated that it is a Schwann cell mitogen and essential for the regeneration of motor neurons in vivo. This project has been designed to study the cell and molecular biology of this novel neuron-glia signalling molecule and the mechanisms by which it is pro regenerative.
Reg-2 is one member of a family of closely-related proteins. Currently, there are three other known members of the Reg gene family in rodents, with several human Reg-related expressed sequence tags (ESTs) in the public databases. One, Reg-l, is expressed in human developing and Alzheimer's disease affected cerebral cortex. It is likely, therefore, that Reg proteins compose a family of novel neuronal signalling molecules involved in the growth and development of distinct populations of neurons. In order to test this hypothesis, this project will study the expression of all known Reg genes in the developing and regenerating mammalian nervous system and characterise the neurons expressing each gene. We will also examine the distribution of receptors for Reg proteins and the biological effects of disruption of Reg-2 by gene targeting. In addition, we will search for novel Reg-related genes expressed in the nervous system.
This project will provide a significant advance in our understanding of the basic biology underlying the process of motor neuron regeneration, which may also be of significant use in developing diagnostics and treatments for the motor neuron diseases. In addition, this project will investigate the functions of the other members of this novel family of neuronal signalling molecules implicated in neural development, regeneration and pathology.

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UNIVERSITY COLLEGE LONDON
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