PATIENT-ORIENTED RESEARCH IN SKIN AUTOMMUNE DISEASE

描述(摘自申请者的摘要)：这项研究计划的科学重点是两个严重的自身免疫疾病的患者导向研究(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)，在哪里 研究治疗学。目的1：-308a TNFa启动子多态性的作用 在光敏的LE中。他们最近报告说，该基因的-308A多态 与野生型(-308G)等位基因不同，TNFct启动子与 具有光敏形式的LE和介导物显著增加转录 体外对UVB的反应。他们现在提议a)扩大他们的调查范围 皮肤红斑狼疮患者-308A基因多态性及相关的人类白细胞抗原单倍型 增加患者数量并更好地评估DR3连锁的作用 平衡障碍；b)对LE患者进行光测，包括测定血清中的肿瘤坏死因子 从UVB照射区域获得的水泡液，并将其相互关联 存在-308A或G多态的研究结果；以及c)评估 -308a启动子对UVB过度反应的分子机制 通过检测转录因子与该区域的不同结合 多态。这些研究的结果旨在推动 了解病理生理学，并可能建议新的治疗方法 皮肤病。 目的1：对糖皮质激素(GC)节约剂在PV中的应用进行循证评价。 由于她的第三次转诊实践，Werth博士已经发表了几份POR 与光伏相关的项目，特别是涉及治疗干预的项目 减少GC引起的骨质疏松症。他们最近开始招收病人。 进入第一个治疗PV的多中心治疗试验，一个可能致命的 自身免疫性水泡病。而且，这场审判是有前瞻性的， 双盲，安慰剂对照。这项试验评估了 氨苯砜，一种非专利的砜，作为维护阶段的GC节约药 光伏。总的目标是系统研究和改进治疗 严重的水泡病，通过开发一种合作试验的模型 到目前为止在这一领域还不存在，并在培训中使用了这一试验 在K24计划下接受指导的个人。Werth博士已经参与了 POR中对学生、住院医师和初级教员的指导和培训。 她致力于通过皮肤科医学来扩大这些努力。 团契。这项K24翻译授权旨在允许P.I.获得更多 有时间专注于以患者为基础的科学研究，并将提供 Werth博士在POR中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.