HEL-N1 IN NEURONAL RNA PROCESSING AND AUTO IMMUNITY

金博士在培训期间的长期目标是开发一个 研究生涯，侧重于基础科学的方法， 了解神经病学中的临床疾病。 在这两年里， 在分子生物学的奖学金，金博士已经建立了他的 早日实现这一目标。 他成功地学会了 并能够克隆一种新的cDNA编码一种 神经元特异性RNA结合蛋白Hel-N1。 初步研究 表明这种蛋白质结合某些蛋白质的3'非翻译区， 癌基因转录物，即c-myc和c-fos。 作为结合区域， 已经证明mRNA中的蛋白质参与转录 稳定性，Hel-N1和N2之间可能存在令人兴奋的联系。 这些基因的转录后调控。 金博士计划 在他的建议中使用mRNA稳定性测定来研究这种可能性 与重组Hel-N1，并通过进行进一步的结合研究， 更精确地描述蛋白质-RNA相互作用。 这些 调查将要求他学习更先进的方法 包括转染、诱变和组织培养技术。 有趣的是，Hel-1和Hel-2之间存在密切的氨基酸序列同源性。 N1和参与副肿瘤、自身免疫综合征的几种抗原 中枢神经系统（CNS）。 通常与小细胞有关 肺癌，这些综合征涉及免疫介导 中枢神经系统（CNS）内多个部位（包括背根）的破坏 神经节、海马、小脑和脊髓。 金博士将 研究氨基酸序列相似性的意义， 这些抗原的免疫学差异和 它们产生的异质性临床综合征。 这将涉及 使用来自这些综合征患者的血清进行表位分析。 此外，他还将测试Hel-N1诱导CNS的能力， 在易感大鼠品系中的自身免疫反应， 用重组纯化蛋白免疫。 该动物模型 将允许更详细地了解这些综合征的机制， S. 总之，这项提案的资金将为金博士提供一个 一个很好的机会来研究Hel-N1的功能， 科学和临床水平。 这也会给他足够的时间 成为一名成熟的独立临床研究者

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.