PATIENT-ORIENTED RESEARCH IN SKIN AUTOMMUNE DISEASE

描述（摘自申请人摘要）：本申请的科学重点 一项研究建议是在两个严重的自身免疫性疾病中进行以患者为导向的研究（POR）。 皮肤病，红斑狼疮（LE），他们一直在调查 病因学和遗传学，以及寻常型天疱疮（PV）， 研究治疗学目的1：-308A TNF α启动子多态性的作用 在光敏LE中。他们最近报道说， 与野生型（-308G）等位基因不同，TNFct启动子与 与光敏形式的LE和介导显着增加转录 在体外对UVB的响应。他们现在建议a）扩大他们的调查， 皮肤LE患者的-308A多态性和相关的HLA单倍型， 增加患者数量，更好地评估DR 3连锁的作用 B）具有LE的光测试患者，包括在患者中测量TNFa; 从UVB照射区域获得的水疱液，并将其与 -308 A或G多态性的存在的发现;和c）评估 -308A启动子对UVB反应过度的分子机制， 通过检测转录因子与细胞核区域的差异结合， 多态这些研究的结果旨在推动 病理生理学的理解，并可能建议新的治疗方法， 皮肤LE。 目的1：循证评价糖皮质激素（GC）保留剂在PV。 由于她的三级转诊实践，Werth博士发表了几篇POR 与PV相关的项目，特别是涉及治疗干预的项目， 最大限度地减少GC引起的骨质疏松症。他们最近开始招募病人 进入首个多中心PV治疗试验， 自身免疫性水疱病另外，这个试验是前瞻性的， 双盲安慰剂对照该试验评估了 氨苯砜，一种非专利砜，作为维持阶段的GC保留药物 的PV。总的目标是系统地研究和改善 通过开发一种合作试验模型， 迄今为止，在这一领域还不存在， 在K24计划下接受指导的个人。沃思博士参与了 对POR的学生、住院医师和初级教员进行指导和培训。 她致力于扩大这些努力与医学皮肤病学 奖学金。这个K24翻译补助金旨在允许P.I.更大 时间专注于以患者为基础的科学研究，并将提供一个 Werth博士在POR追求和指导的基础设施。

DESCRIPTION (Taken from the applicant's abstract): The scientific focus of this research proposal is patient-oriented research (POR) in two serious autoimmune skin diseases, lupus erythematosus (LE), where they have been investigating etiology and genetics, and pemphigus vulgaris (PV), where they are investigating therapeutics. Aim 1: Role of the -308A TNFa promoter polymorphism in photosensitive LE. They recently reported that the -308A polymorphism of the TNFct promoter, unlike the wild-type (-308G) allele, is strongly associated with a photosensitive form of LE and mediates markedly increased transcription in vitro in response to UVB. They now propose to a) expand their survey of cutaneous LE patients for the -308A polymorphism and related HLA haplotypes, to increase the numbers of patients and better evaluate the role of DR3 linkage dysequlibrium; b) phototest patients with LE, including measurement of TNFa in blister fluid obtained from UVB-irradiated regions, and correlate their findings with the presence of the -308A or G polymorphisms; and c) evaluate molecular mechanisms for the exaggerated response of the -308A promoter to UVB, by examining differential binding of transcription factors to the area of the polymorphism. The results of these studies are intended to advance the pathophysiologic understanding and may suggest new treatments for patients with cutaneous LE. Aim 1: Evidence-based evaluation of a glucocorticoid (GC)-sparing agent in PV. Because of her tertiary referral practice, Dr. Werth has published several POR projects related to PV, particularly involving therapeutic interventions to minimize GC-induced osteoporosis. They have recently begun enrolling patients into the first multicenter therapeutic trial for PV, a potentially fatal autoimmune blistering disease. Moreover, this trial is prospective, double-blinded, and placebo-controlled. The trial evaluates the role of dapsone, an off-patent sulfone, as a GC-sparing drug in the maintenance phase of PV. The overall goal is to systematically study and improve the treatment of severe blistering disease, by developing a model for collaborative trials that have not existed in this area to date and by using this trial in the training of individuals mentored under the K24 program. Dr. Werth has been involved in the mentoring and training of students, resident, and junior faculty in POR. She is committed to expanding these efforts with a medical dermatology fellowship. This K24 translational grant is intended to permit the P.I. greater time to focus on patient-based scientific studies and will provide an infrastructure for Dr. Werth to pursue and mentor in POR.