Purinergic Pathways in Crohn's Disease

描述（由申请人提供）：Moss博士是炎症性肠病（IBD）的初级研究员。作为一名研究员，他除了接受胃肠病学家的临床培训外，还接受了炎症分子生物学方面的培训。在过去的2年里，他一直在免疫学研究方法方面接受Simon Robson博士的指导。他的近期目标是进一步发展他在转化研究中的免疫学和研究培训，以研究内源性免疫抑制途径在IBD中的作用。为这些疾病患者开发未来的诊断和治疗工具将需要能够将免疫学的进步带到床边的研究人员，反之亦然。他的中期目标是为R01在该领域的成功应用获得合适的初步数据，并通过相关的学术活动建立他的声誉。从长远来看，Moss博士打算获得持续的资金，以维持一个独立的实验室小组，专注于IBD新疗法和诊断方法的转化研究。 该K23的研究职业发展计划基于免疫学杰出导师（Simon Robson博士），具有强大翻译研究简历的研究人员职业发展委员会以及为促进Moss博士的独立之路而量身定制的特定课程的组合。主办机构（BIDMC）已经通过他晋升为初级教师和助理教授，继续提供实验室空间，保护研究时间（工资支持），并为他提供专门的导师，证明了他们对莫斯博士的持续承诺。医学系和消化科限制了他的临床工作量，主要目的是让他有适当的时间进行实验室经验，课程和学术网络。 拟议的项目不仅是一个具有深远临床意义的主题，而且是一个理想的培训工具，Moss博士将有机会巩固他现有的技能，并学习新的研究技术。Alan Moss博士提出的K23建议的目的是研究克罗恩病患者免疫调节途径改变的机制，以及某些治疗方法如何改变这种效果。特别是，该提案将研究一组酶（CD39，CD73）和受体，这些酶和受体将组织损伤的有害产物（ATP，ADP）转化为免疫抑制分子（腺苷）。在动物模型中的研究表明，这些酶对炎症有保护作用，但它们在人类克罗恩病中的作用尚不清楚。Moss博士的初步数据已经观察到克罗恩病患者中这些酶的比例和活性发生了变化。在这个提议中的实验将量化克罗恩病患者和健康对照中这些嘌呤能通路的存在和活性。我们将研究炎症状态如何损害它们的作用，以及某些药物（抗TNF药物）治疗如何改变它们的活性。该项目旨在提供对克罗恩病患者的这些途径的全面了解，以便开发新的治疗方法来增强其免疫抑制作用。 公共卫生相关性：炎症性肠病影响近200万美国人。这一建议将提高我们对克罗恩病患者免疫系统调节的理解。它可能为患有这种疾病的患者提供新的药物治疗靶点。

DESCRIPTION (provided by applicant): Dr. Moss is a junior investigator in Inflammatory Bowel Disease (IBD). As a fellow he trained in the molecular biology of inflammation, in addition to his clinical training as a gastroenterologist. In the last 2 years he has been mentored by Dr Simon Robson in immunology research methods. His immediate goal is to further develop his immunology and research training in translational research in order to investigate the role of endogenous immuno-suppressive pathways in IBD. The development of future diagnostic and therapeutic tools for patients with these diseases will require investigators who can bring advances in immunology to the bed-side, and vice versa. His medium- term goal is to acquire suitable preliminary data for a successful R01-application in this field, and establish his reputation through relevant scholarly activities. In the long-term Dr Moss intends to obtain consistent funding to maintain an independent laboratory group focused on translational research in novel therapeutics and diagnostic methods in IBD. The research career development plan for this K23 is based on a combination of an outstanding mentor in immunology (Dr Simon Robson), a Career Development Committee of investigators with strong translational research resumes, and specific coursework tailored to foster Dr Moss's pathway to independence. The host institution (BIDMC) have demonstrated their on-going commitment to Dr Moss through his promotion to junior faculty and Assistant Professor, the continued provision of laboratory space, protected research time (salary support), and dedicated mentorship for him. The Dept of Medicine and Division of Gastroenterology have limited his clinical workload with the primary intention of allowing him appropriate time for laboratory experience, coursework and academic networking. The proposed project is not only a topic of profound clinical importance but also an ideal training vehicle in which Dr Moss will have the opportunity to solidify his existing skills and to learn new research techniques. The purpose of this K23 proposal by Dr Alan Moss is to examine the mechanisms through which one pathway of immune regulation is altered in patients with Crohn's disease, and how certain treatments modify this effect. In particular, this proposal will study a group of enzymes (CD39, CD73) and receptors that convert harmful products of tissue damage (ATP, ADP) to immuno- suppressive molecules (adenosine). Studies in animal models have suggested that these enzymes are protective against inflammation, but their role in human Crohn's disease is unknown. Preliminary data by Dr Moss has observed an alteration in the proportion and activity of these enzymes in patients with Crohn's disease. The experiments in this proposal will quantify the presence and activity of these purinergic pathways in patients with Crohn's disease, and healthy controls. We will examine how inflammatory states may impair their action, and how treatment with certain drugs (anti- TNF agents) modifies their activity. This project aims to provide a thorough understanding of these pathways in patients with Crohn's disease, so that novel treatments may be developed to enhance their immuno-suppressive roles. PUBLIC HEALTH RELEVANCE: Inflammatory Bowel Disease affects nearly 2 million Americans. This proposal will improve our understanding of regulation of the immune system in patients with Crohn's disease. It may provide novel targets for drug treatments for patients with this condition.