Assessment in Morphea for the Establishment of Non-Cutaneous Disease (AMEND)

描述(申请人提供)：此申请的目的是支持我在以患者为导向的研究方面的高级培训，目标是成为一名独立资助的研究人员，研究成人和儿童吗啡的流行病学、免疫学和遗传学。我将在德克萨斯大学西南医学中心(我的机构)丰富和支持性环境的帮助下实现这一目标，其中包括：一个代表我感兴趣领域的全国专家的经验丰富的指导委员会；一个强大的培训机构，通过临床科学部的临床学者计划；以及NIH NCRR颁发的支持临床研究的临床和转换科学奖(CTSA)。这些地方资源得到了休斯顿德克萨斯大学健康科学中心的补充，该中心也获得了由我的一位主要导师Frank Arnett博士指导的TSA奖。本文详述的培训计划以及拟议的研究代表了两个地理上相邻的CTSA中心之间的首次合作努力；这是CTSA奖项的一项任务和优先事项。皮肤科承诺全力支持我作为临床研究员的培训，赞助我参加临床学者计划(该计划需要工资支持和75%的保护时间来进行培训和研究项目)，进入部门临床研究中心及其杰出的研究协调员，以及为学科招募提供积极的皮肤科实践。我将结合我在临床研究中的正式培训进行指导研究项目，内容涉及吗啡的流行病学、自身抗体谱和免疫遗传学。吗啡的特征是皮肤增厚和硬化，对成人和儿童都有影响，并有严重的后遗症，如关节、肢体和面部畸形，导致疼痛和功能障碍。目前，关于吗啡对自身免疫性或全身性其他疾病的发展风险的确切影响，是否存在与疾病相关的特征自身抗体或HLA型，可以预测疾病的活动或结果，以及疾病的自然病史，存在争议。这种混乱影响了对吗啡患者的适当治疗，他们因治疗过度或治疗不足而遭受严重后果。在获得这一领域的初步研究经验后，我的目标是进行一项病例对照研究，研究吗啡患者与健康人和硬皮病(推测为系统性吗啡)对照的系统性和自身免疫性疾病的发生率、自身抗体的存在以及与人类白细胞抗原的相关性。在研究的第一阶段登记的吗啡受试者将被要求继续进行前瞻性队列研究，以确定疾病的自然病史，以及在基线测量的特征是否预测了这些结果。这项研究的设计和实施以及上面列出的培训活动将发展流行病学研究的技能以及必要的翻译研究技能，以调查我的发现的机械方面，包括免疫遗传学、自身抗体表征和遗传流行病学，从而开始作为一名独立临床研究员的成功职业生涯。

DESCRIPTION (provided by applicant): The purpose of this application is to support my advanced training in patient-oriented research with the goal of becoming an independently funded investigator studying the epidemiology, immune profiles, and genetics of morphea in adults and children. I will achieve this objective with the help of a rich and supportive environment at the University of Texas Southwestern Medical Center (my institution) which includes: an experienced mentoring committee representing national experts in my fields of interest; a robust training nfrastructure through the Department of Clinical Sciences' Clinical Scholars Program; and an NIH NCRR linded Clinical and Translational Science Award (CTSA) supporting clinical research. These local resources are complemented by the University of Texas Health Science Center in Houston, also the recipient of a TSA award directed by one of my principle mentors, Dr. Frank Arnett. The training program detailed herein as well as the proposed research, represent the inaugural collaborative efforts between two geographically adjacent CTSA centers; which is a mandate and priority for CTSA awards. The Department of Dermatology has committed its full support to my training as a clinical investigator through its sponsorship of my participation in the Clinical Scholars Program (which requires salary support and 75% protected time to pursue training and a research project), access to the departmental clinical research center as well and its outstanding research coordinator, and the active dermatology practice for subject recruitment. The mentored research project that I will conduct in conjunction with my formal training in clinical research nvolves the epidemiology, autoantibody profiles, and immunogenetics of morphea. Morphea is characterized by thickening and hardening of the skin affecting both adults and children and has serious sequelae in terms of joint, limb, and facial deformities producing pain and functional impairment. At this time, there is controversy regarding the exact implications of morphea in terms of its risk for the development of other diseases, either autoimmune or systemic; if there are characteristic autoantibodies or HLA types associated with the disease that may predict disease activity or outcome; and the natural history of the disease. This confusion impairs the appropriate treatment of morphea patients, who suffer serious consequences from either over or under treatment. Having gained initial research experience in this area, I aim to conduct a case control study examining the frequency of systemic and autoimmune disease, presence of autoantibodies, and HLA associations in morphea patients vs. healthy and scleroderma (putatively the systemic form of morphea) controls. Morphea subjects enrolled in the first phase of the study will be asked to continue in a prospective cohort study for ascertainment of the natural history of the disease and if the characteristics measured at baseline predict these outcomes. Design and implementation of this study along with the training activities listed above will develop skills in epidemiological research as well as the translational research skills necessary to investigate the mechanistic aspects of my discoveries including immunogenetics, autoantibody characterization, and genetic epidemiology, thus launching a successful career as an independent clinical investigator.