Grant: Discovery Grants Program - Individual

Nerves in the spinal cord of adult mammals and birds fail to regenerate after injury and correcting this failure is a major goal of neuroscience. Adult newts and salamanders, however, exhibit remarkable regenerative capacity of a number of tissues, including the spinal cord and parts of the brain. Our main research aim is to understand the molecular and cellular mechanisms that underlie functional spinal cord regeneration in the newts as a prelude to determining why mammals fail in this process. To this end, we have examined the role of all-trans retinoic acid (RA), a small, fat-soluble molecule synthesized from vitamin A, in this process. We have recently shown that a protein receptor for RA, retinoic acid receptor beta (RARß), is an important regulator of early events in the regenerating newt spinal cord. However, we do not know what factors are affected by RA-RARß signaling in this process. To regenerate the spinal cord, multiple signaling pathways must be activated or repressed simultaneously, involving numerous molecular changes in RA-responsive cells. We hypothesize that microRNAs (miRNAs), small, non-protein coding RNAs, capable of regulating the expression of many genes coordinately, may be important targets of RA signaling. Our specific objectives are threefold: 1. To identify novel miRNAs synthesized as a consequence of damage to the spinal cord as well as those whose production is affected by retinoid treatment. 2. To determine the cells in the regenerating spinal cord that make these miRNAs and identify their potential messenger RNA targets and functions. 3. Finally, to analyze the mechanism by which RA can guide growing nerves to their appropriate ""target"" cells in regenerating spinal cords. These studies would represent the first comprehensive analysis of the role of miRNAs in regulating RA signaling in a regenerating spinal cord model. It is hoped that our results will provide a more thorough understanding of the molecular events controlling spinal cord regeneration in newts, with the goal of applying this knowledge to the as yet intractable process of spinal cord repair in higher vertebrates, including humans.