Scleroderma and Gastrointestinal Disease: Insights into Clinical Phenotypes and Disease Pathogenesis

项目摘要 博士Zsuzsanna McMahan是约翰霍普金斯大学流变学系的医学助理教授 大学她在风湿病学奖学金培训期间获得了临床研究硕士学位， 她目前得到约翰霍普金斯临床科学家发展奖，杰罗姆L。格林 基金会和NIH贷款偿还计划。她的共同主要导师是弗雷德里克威格利博士，一个 具有硬皮病（SSc）专业知识的国际公认的风湿病学家和Livia Casciola-Rosen博士， 他是国际公认的细胞生物学家，具有鉴定新型自身抗体的专业知识。安东尼博士 罗森是约翰霍普金斯大学流变学系主任兼研究副主任， 她在翻译调查方面拥有丰富的专业知识，也是她指导团队的一员。麦克马汉博士创造了 由具有特定专业领域的导师和顾问组成的杰出咨询委员会 这与提案有关。其中包括米歇尔·佩特里博士（纵向队列）和克利夫顿·宾厄姆博士 （患者报告的结果）在风湿病学，詹姆斯罗素博士在神经病学（自主神经功能障碍），和博士。 Jay Pasricha在胃肠病学（动力障碍）。他们将提供专门针对其专业领域的指导。 该咨询委员会对该提案非常热情，并全力投入指导McMahan博士。 K23奖将使McMahan博士获得对翻译行为重要的额外技能。 研究，发展神经胃肠病学的特定利基专业知识，因为它涉及SSc，并获得 数据和出版物，以支持强大的R 01应用程序。在这份提案中，麦克马汉博士试图 使用基于放射性核素的整体分析方法精确定义SSc胃肠（GI）动力障碍的解剖学子集 肠道转运研究，将GI运动障碍亚群与传统SSc抗体和靶向 神经肌肉传递途径，并最终确定新的自身抗原靶向SSc血清在胃肠道。 SSc中的自身抗体与临床表型密切相关，并可作为危险分层的有用标志物。 目前，SSc GI疾病的风险分层是有限的，与GI相关的自身抗体很少。 并发症显然，GI亚群的表型分析将为在更广泛的范围内研究疾病机制提供平台。 同质SSc GI亚群，并提供了一个框架，从长远来看，探索新的治疗方法。 博士McMahan已经产生了强有力的初步数据，这些数据支持以下观点：（1） SSc患者存在胃肠道动力障碍;（2）患者存在抗神经肌肉传递途径的自身抗体 与SSc相关，可能与特定的GI结果相关;（3）来自运动障碍患者的SSc血清识别 不同的细胞亚群。她建立了强有力的跨部门合作， 提供所需的支持和专业知识，以指导她，并确保完成和适当的解释 的拟议研究。这些研究的结果将为今后的工作创造一个平台， 生物学机制，定义疾病活动的生物标志物，并探索新的治疗方法。

PROJECT ABSTRACT Dr. Zsuzsanna McMahan is an Assistant Professor of Medicine in the Division of Rheumatology at Johns Hopkins University. She obtained her Masters in Clinical Investigation during her rheumatology fellowship training, and she is currently supported by the Johns Hopkins Clinician Scientist Development Award, the Jerome L. Greene Foundation, and the NIH Loan Repayment Program. Her co-primary mentors are Dr. Fredrick Wigley, an internationally recognized rheumatologist with expertise in scleroderma (SSc), and Dr. Livia Casciola-Rosen, an internationally recognized cell biologist with expertise in the identification of novel autoantibodies. Dr. Antony Rosen, the Director of the Division of Rheumatology, and Vice Dean for Research at Johns Hopkins, has significant expertise in translational investigation, and is also part of her mentoring team. Dr. McMahan created an outstanding Advisory Committee comprised of mentors and consultants who have specific areas of expertise which are relevant to the proposal. These include Drs. Michelle Petri (longitudinal cohorts) and Clifton Bingham (patient reported outcomes) in rheumatology, Dr. James Russell in neurology (autonomic dysfunction), and Dr. Jay Pasricha in gastroenterology (dysmotility). They will provide guidance specific to their area(s) of expertise. This Advisory Committee is highly enthusiastic about the proposal and fully invested in mentoring Dr. McMahan. The K23 award will enable Dr. McMahan to gain additional skills important for the conduct of translational research, develop expertise in the specific niche of neurogastroenterology as it pertains to SSc, and acquire the data and publications necessary to support a strong R01 application. In this proposal, Dr. McMahan seeks to precisely define anatomical subsets of SSc gastrointestinal (GI) dysmotility using a radionucleotide-based whole gut transit study, associate the GI dysmotility subsets with traditional SSc antibodies and antibodies that target neuromuscular transmission pathways, and finally define novel autoantigens targeted by SSc sera in the GI tract. Autoantibodies in SSc associate tightly with clinical phenotypes and serve as useful markers in risk stratification. Currently, risk stratification in SSc GI disease is limited, with few autoantibodies associated with GI complications. Clearly phenotyping GI subsets will provide a platform to study disease mechanism within more homogenous SSc GI subsets and provide a framework from which to explore novel therapies in the longer term. Dr. McMahan has generated strong preliminary data, which supports the following ideas: (1) specific patterns of GI dysmotility exist in SSc; (2) autoantibodies to neuromuscular transmission pathways are present in patients with SSc and may associate with specific GI outcomes; and (3) SSc sera from patients with dysmotility recognize distinct cellular subsets in the GI tract. She has established strong inter-departmental collaborations that will provide the required support and expertise to guide her and ensure the completion and appropriate interpretation of the proposed studies. The results of these studies will create a platform for future work aimed at evaluating biological mechanism, defining biomarkers of disease activity, and exploring novel therapies.