Studies of Estrogen Receptors in Autoimmunity

这是一份修订后的以指导病人为导向的发展奖申请，使wael N. Jarjour博士能够在五年内将75%的时间投入到一个包括教学课程和实验室调查的项目中，使他能够获得生物统计学、人体调查、研究设计和实验调查方面的培训。这个项目将促进他的职业发展，成为一名独立的临床研究者。本课程包括基础统计学、高级统计建模、临床调查的基本方法和临床调查的道德行为的强化课程。他将接受margaret Shupnik博士作为主要导师的分子内分泌学和Shu Man Fu博士作为共同导师的细胞免疫学的培训。已经成立了一个委员会来监督他的进展和内科系主任的承诺，即有75%的保护时间来实现该奖项所概述的目标。系统性红斑狼疮（SLE）主要影响女性，肾脏是主要的靶器官之一，一项研究计划旨在解决关于性别偏见的重要问题。考虑到审稿人的顾虑，研究计划已被修改。它涉及雌激素受体（ER）在SLE发病机制中的作用。这种疾病主要影响生育期的女性。研究还表明，雌性激素（如雌激素）对免疫系统有深远的影响。因此，研究雌激素受体在系统性自身免疫的原发疾病SLE中的作用是合乎逻辑的。初步数据表明，正常人和SLE患者淋巴细胞中α和β雌激素受体的表达存在显著差异。提出了四个具体目的：1)与健康对照比较SLE患者循环T细胞中erα和erβ的蛋白和mRNA表达；2)确定SLE患者和对照组的T淋巴细胞ER活化是否不同；3)确定SLE患者和某些正常对照人群的T细胞敏感性改变是否由于调节ER活性的odf蛋白的影响。该研究计划将为Jarjour博士提供实验设计和技术、数据分析和手稿准备方面的必要培训，并补充教学课程。通过教学课程和实验室研究，Jarjour博士将实现他的目标，成为一名独立的临床研究者，能够研究人类免疫基础疾病的机制，并根据对这些机制的理解设计新的治疗方法。

This is an amended application for a mentored patient-oriented development award to enable Dr.Wael N. Jarjour to devote 75% of his time for five years to a program that includes didactic coursework and laboratory investigatiion to enable him to obtain training in biostatistics, human investigation, research design and experimental investigation. This program will facilitate his career development to be an independent clinical investigator. This program consists of didactic coursework involving basic statistics, advanced statistical modeling, fundamental methodologies in clinical investigation, and a intense course in ethical conduct of clinical investigation. It is proposed that he will be trained in molecular endocrinology by Dr.Margaret Shupnik who will serve as primary mentor, and in cellular immunology by Dr. Shu Man Fu as his co-mentor. A committee has been set up to monitor his progress and the commitment from the Chair of the Department of Internal Medicine to have 75% protected time to achieve the goals as outlined for this award. A research program has been devised which addresses an important issue regarding gender bias in systemic lupus erythematosus (SLE) which affects females predominately and the kidney as one of the major target organs. The research plan has been revised taking the Reviewers' concerns in to consideration. It deals with the role of estrogen receptors (ER) in the pathogenesis of SLE. This disease affects predominately females in their reproductive life. It has also been demonstrated that female hormones such as estrogen have profound effects on the immune system. Thus, it is logical to study the role of estrogen receptors in SLE, a protyppic disease of systematic autoimmunity. Preliminary data have suggested marked differences between alpha nd beta estrogen receptor expression by lymphocytes from normals and SLE patients. Four specific aims are proposes: 1) to examine the protein and mRNA expression of ERalpha and Erbeta in circulating T cells of patients with SLE in comparison with healthy controls; 2) to determine if ER activation differs in T lymphocytes from SLE patients and controls; and 3) to determine whether altered sensitivity of T cells from SLE patients and certain normal control populations is due to the effects odf protein which regulate ER activty. This research plan will provide Dr. Jarjour the needed training in experimental design and techniques, data analyses, and manuscript preparation as well as to complement the didactic coursework. Through both didactic coursework and laboratory investigation, Dr. Jarjour will attain his goals to develop into an independent clinical investigator with ability to study mechanisms of human diseases of immunological basis and to devise novel therapeutic approaches based on the understanding of these mechanisms.