The Role of Gut and Skin Microbiome in Psoriatic Arthritis

职位描述(申请人提供)：近期和长期的职业目标：何塞·U·谢尔，医学博士，在临床免疫学和风湿学以及基础和翻译研究方面有很强的背景。他的主要职业目标是成为一名独立的学术研究科学家，在因果发现方法领域从事风湿病、免疫学、微生物学和计算分析之间的工作。为了实现这一长期目标，舍尔博士计划通过一项计划，将他的研究领域扩展到医学领域，以获得组学和计算专业知识，并学习大数据集上下游分析的基本技能。环境-研究职业发展计划的关键要素：Scher博士目前是纽约大学医学院风湿病学部医学系的初级教员。在导师团队(导师Steven B.Abramson博士；共同导师Constantin Avenis博士)、合作者(Martin Baser博士、Andrea Neimann博士、Jonathan Samuels博士)和顾问的指导下，Scher博士将参加一项严格的培训计划，包括：1)高级计算分析方面的实践研究培训；2)通过研究生课程进行高级因果路径发现方法、计算研究、生物统计学和临床试验设计的正式教学培训；3)在导师、合作者和顾问的研究小组中为期刊俱乐部和小组会议做出贡献；4)参加国内和国际会议和研讨会；以及5)参加负责任地开展研究的培训课程。研究项目：银屑病关节炎(PSA)是一种病因不明的慢性炎症性疾病，约三分之一的人患有牛皮癣(影响2-3%的人口)。肠道和皮肤微生物区系(栖息的微生物总数 在人体内/在人体上)长期以来一直被认为是炎症性疾病的诱因，在动物模型和人类中的多项报告表明，在自身免疫和风湿病的表现中起主导作用。有强有力的遗传、临床和基于治疗的证据表明，牛皮癣、牛皮癣关节炎和炎症性肠道疾病是相同疾病谱的例子。鉴于长期考虑的假设，即细菌感染可能是PSA发展的环境触发因素，应用现代微生物学技术和因果发现方法来评估这一问题可能会对该领域产生重大影响。因此，我们建议利用最先进的、独立于培养的DNA测序技术结合复杂的计算分析工具来研究肠道和皮肤微生物区系在PSA中的作用。我们的主要假设是：1)人类肠道/皮肤中微生物的特征将有助于深入了解疾病的发病机制；2)肠道/皮肤微生物区系与局部和全身免疫反应有关，可能导致(并预测)从皮肤银屑病到PSA的过程。所获得的见解可能会阐明微生物群落如何与宿主肠道/皮肤成分相互作用，并为开发新的PSA诊断和治疗方法提供理论基础。目的1)研究PSA患者肠道微生物区系与局部肠道免疫反应之间的关系，探讨肠道微生物区系在初发银屑病关节炎中的作用。目的2)通过以下方式确定皮肤微生物区系在新发的PSA中的作用：a)研究皮肤微生物区系的改变是否与银屑病患者的表型差异相关 与PSA患者比较；以及b)研究PSA患者皮肤微生物区系与全身免疫反应之间的关系。还将追求另一个次级目标，目标3，以便a)扩大已建立的用于研究PSA自然历史的纵向数据库/生物储存库，以及b)调查基线皮肤和/或肠道微生物区系是否可以预测关节炎/末端炎的发展。精心选择的结果应该允许我们将特定微生物或微生物组模式的存在与免疫反应、其他特定生物标志物和临床活动的变化联系起来。相关性：该项目与美国国立卫生研究院的一项主要路线图计划--人类微生物组计划的目标一致，并有可能通过填补有关炎症性关节炎病因的基本知识空白而真正实现变革。这一结果可能会改变我们对微生物和人类之间关系的理解，并导致创新的诊断测试和未来的治疗方法。

DESCRIPTION (provided by applicant): Immediate and Long-Term Career Goals: Jose U. Scher, MD, has a strong background in clinical immunology and rheumatology, as well as basic and translational research. His overarching career goal is to become an independent academic research scientist working at the interface between rheumatic diseases, immunology, microbiology, and computational analytics in the area of causal discovery methods. To achieve this long-term goal, Dr. Scher plans to extend his research area into the medical sciences through a plan for acquiring 'omics and computational expertise, as well as learning essential skills for upstream and downstream analysis of large datasets. Environment - Key Elements of the Research Career Development Plan: Dr. Scher is currently a junior faculty member in the Department of Medicine, Division of Rheumatology at New York University School of Medicine. Under the guidance of the mentoring team (mentor Dr. Steven B. Abramson; co-mentor Dr. Constantin Aliferis), collaborators (Drs. Martin Blaser, Andrea Neimann, Jonathan Samuels) and advisors, Dr. Scher will enter a rigorous training program consisting of: 1) hands-on research training in advanced computational analytics; 2) formal didactic training via graduate courses in Advanced Causal Pathway Discovery Methods, Computational Studies, Biostatistics, and Clinical Trials Design; 3) contribution to journal clubs and group meetings in the research groups of the mentors, collaborators and advisors; 4) participation in national and international conferences and symposia; and 5) participation in training courses in the responsible conduct of research. Research Project: Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown etiolology, occurring in about one third of people with psoriasis of the skin (a condition that affects 2-3% of the population). Gut and skin microbiota (the totality of microbes that reside in/on the human body) have long been thought to contribute to inflammatory diseases, and multiple reports in animal models and humans suggest a predominant role in autoimmune and rheumatic disease manifestations. There is strong genetic, clinical and therapy-based evidence that psoriasis, psoriatic arthritis and inflammatory bowel diseases represent examples of the same disease spectrum. Given the long-considered hypothesis that bacterial infection could represent an environmental trigger for PsA development, the application of modern microbiology technologies and causal discovery methods to assess this question could have significant impact on the field. We therefore propose to study the role of intestinal and skin microbiota in PsA utilizing state-of-the-art, culture-independent, DNA sequencing techniques coupled with sophisticated computational analytical tools. Our primary hypotheses are that: 1) characterization of microbes in human intestine/skin will provide insight into disease pathogenesis; and 2) gut/skin microbiota are associated with local and systemic immune responses potentially responsible for (and predictive of) the passage from psoriasis of the skin to PsA. Insights attained may elucidate how microbial communities interact with host intestinal/cutaneous components and provide a rationale for the development of new diagnostic and therapeutic approaches for PsA. Two primary Specific Aims are proposed: Aim 1) To study the role of intestinal microbiota in new-onset Psoriatic Arthritis by: a) characterizing the alterations of skin microbiota community at the onset of PsA; and b) studying the link between intestinal microbiota in PsA patients and the local intestinal immunologic response. Aim 2) To determine the role of skin microbiota in new- onset PsA by: a) investigating whether alterations in the skin microbiota correlate with phenotypic differences in patients with psoriasis of the skin versus PsA patients; and b) studying the association between skin microbiota in PsA patients and the systemic immunologic response. An additional secondary aim, Aim 3, will also be pursued in order to a) expand an established longitudinal database/biorepository for the study of natural history of PsA and b) investigate whether baseline skin and/or gut microbiota can predict development of arthritis/enthesitis. Carefully selected outcomes should permit us to correlate the presence of a specific microorganism or microbiome pattern with changes in immune response, other specific biomarkers, and clinical activity. Relevance: This project is consistent with the goals of the Human Microbiome Project, a major NIH Roadmap initiative, and has the potential to be truly transformative by filling a fundamental knowledge gap regarding the cause of inflammatory arthritis. The results could transform our understanding of the relationships between microbes and humans, and lead to innovative diagnostic tests and future treatments.