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

项目摘要 Zsuzsanna McMahan博士是约翰霍普金斯大学风湿病学部的医学助理教授 大学。她在风湿学研究员培训期间获得了临床调查硕士学位，并 她目前得到了约翰霍普金斯大学临床医生科学家发展奖杰罗姆·L·格林的支持 基金会和美国国立卫生研究院贷款偿还计划。她的联合小学导师是弗雷德里克·威格利博士，一位 具有硬皮病(SSC)专业知识的国际公认的风湿病专家和Livia Casciola-Rosen博士，以及 在鉴定新型自身抗体方面具有专业知识的国际公认的细胞生物学家。安东尼博士 罗森是约翰·霍普金斯大学风湿科主任兼研究副院长，他说 在翻译调查方面拥有丰富的专业知识，也是她的指导团队的一员。麦克马汉博士创造了 一个杰出的咨询委员会，由具有特定专业领域的导师和顾问组成 这些都是与提案相关的。这些人包括米歇尔·佩里博士(纵向队列)和克利夫顿·宾汉姆 (患者报告的结果)，詹姆斯·罗素博士在神经病学(自主神经功能障碍)， Jay Pasricha在胃肠病学(运动障碍)。他们将针对自己的专业领域(S)提供指导。 本咨询委员会对这项建议非常热情，并全力指导McMahan博士。 K23奖将使McMahan博士获得对进行翻译非常重要的其他技能 研究，开发与SSC相关的神经胃肠病学特定利基领域的专业知识，并获得 支持强大的R01应用程序所需的数据和出版物。在这项提案中，麦克马汉博士试图 使用基于放射性核苷酸的整体精确定义SSc胃肠(GI)运动障碍的解剖亚群 肠道转运研究，将GI运动障碍亚群与传统的SSC抗体和靶向 神经肌肉传递途径，并最终确定胃肠道中SSC血清靶向的新的自身抗原。 SSC中的自身抗体与临床表型密切相关，可作为危险分层的有用标记物。 目前，SSc GI病的风险分层是有限的，很少有与GI相关的自身抗体 并发症。显然，表型GI亚群将提供一个平台，在更多的 同质的SSC GI亚群，并提供了一个框架，从长期来探索新的治疗方法。 McMahan博士产生了强大的初步数据，这支持以下想法：(1)特定的模式 SSC存在胃肠动力障碍；(2)患者存在抗神经肌肉传递途径的自身抗体 与SSc有关，并可能与特定的GI结果相关；以及(3)来自运动障碍患者的SSC血清 胃肠道中有不同的细胞亚群。她已经建立了强大的跨部门合作，这将 提供所需的支持和专业知识来指导她，并确保完成和适当的解释 建议进行的研究。这些研究的结果将为今后旨在评价 生物学机制，定义疾病活动性的生物标志物，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.