Studies of Estrogen Receptors in Autoimmunity

这是对以患者为导向的发展奖的修订申请，使Wael N.Jarjour博士能够在五年内将75%的时间投入到一个项目中，该项目包括教学课程和实验室调查，使他能够获得生物统计学、人类调查、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员。本课程包括基本统计学、高级统计建模、临床研究的基本方法和临床研究的伦理指导课程。据建议，他将由玛格丽特·舒普尼克博士担任主要导师，接受分子内分泌学方面的培训，并由傅树文博士担任他的联合导师，接受细胞免疫学方面的培训。已经成立了一个委员会，以监测他的进展情况以及内科主任承诺有75%的保护时间来实现该奖项概述的目标。已经制定了一项研究计划，以解决系统性红斑狼疮(SLE)中性别偏见的一个重要问题。系统性红斑狼疮主要影响女性，肾脏是主要靶器官之一。考虑到评审者的担忧，研究计划已经进行了修改。它涉及雌激素受体(ER)在SLE发病机制中的作用。这种疾病主要影响女性的生殖生活。研究还表明，雌激素等女性荷尔蒙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性疾病SLE中的作用是合乎逻辑的。初步数据表明，正常人和系统性红斑狼疮患者淋巴细胞的α和β雌激素受体表达存在显著差异。本研究的目的有四个：1)检测SLE患者外周血T细胞中ERα和ERβ的蛋白和mRNA表达，并与健康对照组比较；2)确定SLE患者和正常对照T淋巴细胞ER活性是否存在差异；3)确定SLE患者和某些正常对照T细胞的敏感性改变是否与调节ER活性的蛋白作用有关。这项研究计划将为Jarjour博士提供在实验设计和技术、数据分析和手稿准备方面所需的培训，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，发展成为一名独立的临床调查员，有能力研究人类疾病的免疫学基础的机制，并在了解这些机制的基础上设计出新的治疗方法。

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.