This proposal concerns the continued study of neurotrophins (NTFs) and their receptors, via the analysis of diverse mouse models as a means to understand neural development. Trk family receptor tyrosine kinases and their ligands, the NTFs, have been implicated in neuronal survival and differentiation. NTFs have been considered as potential therapeutic agents for neurodegenerative diseases including Alzheimer's & ALS as well as for spinal cord injury. In the previous period, we generated a variety of Trk receptor & NTF mutant mice. Study of these mice has provided valuable information regarding the in vivo function of NTFs in neuronal survival. We proposed to continue these studies &in the First Aim will continue to study NTF function in sensory neuron development and survival. We will further exploit these mutant mice to continue preliminary analysis of NTF requirement in development of the olfactory, and gustatory systems. We will also perform a detailed comparative analysis of our null trkC & NT-3 mutants with a Kinase null trkC mutant. These proposed studies for the first time directly address the in vivo function of truncated receptors. In the Second Aim we will identify the determinants that regulate the NGF receptor, TrkA. This enhancer analysis will provide novel information about the upstream molecules that regulate neurotrophin receptors & the developing nervous system. In the third aim, we will exploit the existence of a TrkA enhancer, to perform structure/function analysis of the TrkA receptor in vivo. We will in vitro mutate intracellular signaling determinants of TrkA and introduce mutated transgenic receptors into the TrkA-/- mouse. Transgenic embryos will be analyzed for rescue of several defined parameters. This approach will reveal physiologically relevant signaling effectors for survival and differentiation of neurons in vivo. A limitation of NTF knockout studies has been early postnatal lethality. This precludes analysis of function in the adult. In the Fourth Aim, we propose to complete our ongoing conditional Knock Out strategies for TrkB and BDNF which will enable us to expand our studies.
Showing the most recent 10 out of 17 publications
