The Role of Gut and Skin Microbiome in Psoriatic Arthritis

描述（由申请人提供）：近期和长期职业目标：何塞U。Scher博士在临床免疫学和风湿病学以及基础和转化研究方面具有很强的背景。他的总体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性疾病，免疫学，微生物学和计算分析之间的接口工作。为了实现这一长期目标，Scher博士计划通过获取组学和计算专业知识的计划，以及学习大型数据集上游和下游分析的基本技能，将他的研究领域扩展到医学科学。 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医学系流变学系的初级教员。在指导团队的指导下（指导者Steven B博士。艾布拉姆森; Constantin Aliferis博士），合作者（Martin Blaser，Andrea Neimann，Jonathan Samuels博士）和顾问，Scher博士将参加一个严格的培训计划，包括：1）高级计算分析的实践研究培训; 2）通过高级因果通路发现方法，计算研究，生物统计学和临床试验设计的研究生课程进行正式的教学培训; 3）对指导者、合作者和顾问的研究小组的期刊俱乐部和小组会议作出贡献; 4）参加国家和国际会议和研讨会; 5）参加负责任地进行研究的培训课程。 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，发生在约三分之一的皮肤银屑病患者中（影响2-3%的人口）。肠道和皮肤微生物群（居住在 在人体内/人体上）长期以来被认为有助于炎性疾病，并且动物模型和人类中的多个报告表明在自身免疫和风湿性疾病表现中起主要作用。有强有力的遗传、临床和治疗证据表明，银屑病、银屑病关节炎和炎症性肠病代表了相同疾病谱的例子。考虑到细菌感染可能是PsA发展的环境触发因素这一长期假设，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、不依赖于培养的DNA测序技术以及复杂的计算分析工具来研究肠道和皮肤微生物群在PsA中的作用。我们的主要假设是：1）人类肠道/皮肤中微生物的表征将提供对疾病发病机理的洞察;和2）肠道/皮肤微生物群与局部和全身免疫应答相关，所述局部和全身免疫应答可能负责（和预测）从皮肤的银屑病到PsA的通路。所获得的见解可以阐明微生物群落如何与宿主肠道/皮肤成分相互作用，并为PsA的新诊断和治疗方法的开发提供理论基础。提出了两个主要的具体目的：目的1）通过以下方式研究肠道微生物群在新发银屑病关节炎中的作用：a）表征PsA发作时皮肤微生物群的改变;和B）研究PsA患者中肠道微生物群与局部肠道免疫应答之间的联系。目的2）通过以下方式确定皮肤微生物群在新发PsA中的作用：a）调查皮肤微生物群的改变是否与皮肤银屑病患者的表型差异相关 对比PsA患者;和B）研究PsA患者中皮肤微生物群与全身免疫应答之间的关联。还将追求另一个次要目标，即目标3，以便a）扩展用于研究PsA自然史的已建立的纵向数据库/生物储存库，和B）研究基线皮肤和/或肠道微生物群是否可以预测关节炎/附着点炎的发展。仔细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相关联。相关性：该项目与NIH主要路线图计划人类微生物组项目的目标一致，并有可能通过填补有关炎症性关节炎原因的基本知识空白而真正实现变革。这些结果可能会改变我们对微生物与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.