NHLBI CLINICAL INVESTIGATOR AWARD

长期以来，我一直致力于一项学术研究 职业生涯。我的研究经验主要集中在珠蛋白基因调控方面。 虽然我的医学背景包括四年的强化临床培训 内科和血液学。本计划将开发的领域 包括基础科学知识、设定研究优先事项能力和 评估可行性、获得资金和管理实验室的能力以及 能够严谨地解决特定临床问题。 染色质结构是解决珠蛋白临床问题的一种途径 镰状细胞病和β地中海贫血的调控。多流 技术不适用于高等生物体。酵母提供了一种 变通的、基因可操纵的、可以在新的时候探索的系统 研究哺乳动物系统的方法被开发出来。一种新技术，两种 染色质的空间杂交图谱将用于检测 重要的酵母结构蛋白，如HMG和序列特异性 结合蛋白。受调控的基因将被研究在活性和 非活性形式以TYL重复元素开始，并进行到 单拷贝基因。调控突变体、回复突变体和生长缺陷 (CDC)突变体将被研究。限制性内切酶的酶切 将探索染色质。最终，这些技术将被带到 与哺乳动物系统中的珠蛋白调节有关。研究进展 技能将分3个阶段进行。第一个是一门激烈的基础科学 在麻省理工学院瓦尔沙夫斯基博士的实验室里的经历。我会专注于 设计和执行实验，撰写论文，拓宽我的 科学基础。临床接触将通过每周一次的 不到10%的努力的诊所。第二阶段将是 从监督工作过渡到独立工作。与中国的互动 瓦尔沙夫斯基和内森博士都应该帮助平衡临床应用 和科学的严谨性。最后一个阶段是以独立调查员的身份 用严谨的方法探索哺乳动物胎儿到成人的珠蛋白开关 染色质技术。

I have long had a deep and consistent commitment to an academic research career. My research experience has concentrated on globin gene regulation while my medical background includes 4 years of intensive clinical training in internal medicine and hematology. Areas to be developed by this program include basic science knowledge, ability to set research priorities and assess feasibility, ability to obtain funding and administer a lab and the ability to rigorously address questions of specific clinical import. Chromatin structure is one approach to the clinical problem of globin regulation in sickle cell disease and beta thalassemia. Many current techniques are not suitable for higher organisms. Yeast offers an altenative, genetically manipulable, system that can be explored while new approaches to the mammalian system are developed. A new technique, two dimensional hybridization mapping of chromatin will be used to detect important structural yeast proteins, such as HMGs and sequence specific binding proteins. Regulated genes will be studied in both active and inactive forms beginning with the Tyl repetative element and progressing to single copy genes. Regulation mutants, revertants and growth defective (CDC) mutants will be studied. Restriction endonuclease digestion of chromatin will be explored. Eventually these techniques will be brought to bear on globin regulation in mammalian systems. Development of research skills will be in 3 phases. The first is an intense basic science experience in the lab of Dr. Varshavsky at MIT. I will concentrate on designing and performing experiments, writing papers and broadening my scientific base. Clinical contact will be maintained through a weekly clinic involving less than 10% effort. The second phase will be a transition from supervised work toward independence. The interaction with both Drs. Varshavsky and Nathan should help balance clinical applications and scientific rigor. The final phase is as an independent investigator exploring the mammalian fetal to adult globin switch with rigorous chromatin technology.