HEL-N1 IN NEURONAL RNA PROCESSING AND AUTO IMMUNITY

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Dr. King's long term goal during this training period is to develop a research career that focuses on basic science approaches to understanding clinical disease in neurology. During the two year fellowship in molecular biology, Dr. King has already established his early commitment to that goal. He successfully learned the fundamentals of molecular biology and was able to clone a novel cDNA encoding a neuronal-specific RNA binding protein named Hel-N1. Preliminary studies indicate that this protein binds the 3' untranslated regions of certain oncogene transcripts, namely c-myc and c-fos. As the region of binding within the mRNA has already been shown to be involved in transcript stability, there is potentially an exciting link between Hel-N1 and the post-transcriptional regulation of these genes. Dr. King plans to investigate this possibility in his proposal using mRNA stability assays with recombinant Hel-N1 and by performing further binding studies to characterize more precisely the protein-RNA interaction. These investigations will require that he learn more advance approaches including transfections, mutagenesis and tissue culture techniques. Interestingly, there is close amino acid sequence homology between Hel- N1 and several antigens involved in paraneoplastic, autoimmune syndromes of the central nervous system (CNS). Most often related to small cell carcinoma of the lung, these syndromes involve immune mediated destruction of various loci within the CNS, including dorsal root ganglia, hippocampus, cerebellum and spinal cord. Dr. King will investigate the significance of the amino acid sequence similarities and differences with respect to the immunology of these antigens and the heterogeneous clinical syndromes they produce. This will involve epitope analysis using sera from patients with these syndromes. Moreover, he will also test the ability of Hel-N1 to induce a CNS autoimmune response in susceptible rat strains through the use of immunizations with recombinant, purified protein. This animal model will allow for more detailed understanding of the mechanism of these syndro s. In summary, the funding of this proposal will provide Dr. King an excellent opportunity to study the function of Hel-N1 both on a basic science and clinical level. It will also allow him the time necessary to mature as an independent clinical investigator.