The long range goal of this research program is to identify the requirements of developing and mature CNS neurons for survival and axonal regeneration after injury and to identify ways to enhance regenerative growth after spinal cord injury at birth and at maturity. It is likely that both intrinsic neuronal and extrinsic environmental factors contribute to regenerative success or failure in particular populations of neurons. We hypothesize that interventions (transplants and neurotrophic factors) which increase regrowth of axons after spinal cord injury do so by: a) altering the response of injured neurons to neurotrophins via changes in neurotrophin receptor expression, b) activating specific growth and regeneration associated genes in injured neurons and c) modifying the environment at and below the injury site by altering levels of axon guidance molecules. We predict that there is specificity in the influence of particular neurotrophins on specific populations of injured neurons. We also predict that molecules known to contribute to the normal development of CNS pathways play a role in regeneration after spinal cord injury. The studies proposed seek to 1) define the intrinsic cellular and molecular characteristics of neurons that regenerate successfully after spinal cord lesion in the neonate and in the adult and 2) define the changes in the molecular environment at and caudal to an acute and chronic spinal cord transection. We speculate that changes in both the intrinsic neuronal capacity for regrowth (via neurotrophins and a condition in influence of a second injury) and alterations in the environment caudal to the transection (a decrease in inhibitory factors and/or an increase in molecules that support growth) combine to yield greater regenerative growth after chronic injury than after acute injury. The experiments proposed use spinal cord lesions and transplants in newborn and adult rats and the administration of exogenous neurotrophic support (BDNF, NT-3) to define the cellular and molecular characteristics of neurons that regenerate successfully. We will use ribonuclease protection assays, in situ hybridization, anterograde and retrograde neuroanatomical tracing, immunocytochemistry and quantitative morphometrics to identify changes that occur in the cell bodies of axotomized and regenerating neurons in vivo and in the environment encountered by the regrowing axons. Taken together, the studies proposed in this competing renewal application will increase our understanding of the cellular and molecular mechanisms by which transplants and neurotrophins increase regeneration of axotomized neurons after spinal cord injury at birth and in the adult.
Showing the most recent 10 out of 35 publications
