Role of Dendritic Cell Activation in the Pathogenesis of Liver Fibrosis

描述（由申请人提供）： 我是外科医生兼科学家我的临床兴趣是照顾良性和恶性肝病患者。我的研究兴趣是研究急性慢性肝脏疾病的免疫学变化。我75%以上的时间都花在实验室里。我的主要职业目标是成为肝脏免疫病理学的独立研究者，并能够将我的实验室工作转化为我的患者的临床试验。我的第二个目标是激励其他年轻的医生追求调查事业。我有一个很好的指导系统，为我的早期职业生涯设置。我的导师（艾伦·弗雷）是一位顶尖的免疫学家，我的共同导师（布鲁斯·克朗斯坦）是一位医生，他是慢性肝病发病机制方面的著名权威。我很幸运能与我的导师和共同导师有非常密切的个人关系。我提出的培训计划是通过基础科学（第1年和第2年）的有限的教学式博物馆式课程来增强我对分子发病机制的理解，以及临床研究科学硕士课程，重点是转化医学（第3年和第4年）。后者是由我的共同导师指导的一个项目，其目的是培养临床科学家将科学发现转化为临床环境所需的技能。纽约大学的研究环境非常支持这项工作。作为一个亮点，我们目前有一个多学科的肝脏兴趣小组，每周开会讨论肝病的临床，基础科学和转化概念。 我的研究计划旨在研究肝树突状细胞活化在肝纤维化发病机制中的作用。肝纤维化的发病机制是复杂的，我们对它的发展背后的细胞和生化因素的理解仍然是初步的。肝星状细胞（HSC）是肝纤维化细胞外基质的主要生产者。肝损伤后，包括免疫活性细胞（如T细胞和枯否细胞）在内的细胞类型的多样性相互作用产生一系列细胞因子，包括IL-6、CCL 21、TNF-α和TGF-β，其导致HSC活化、细胞外基质沉积，并最终进展为肝纤维化和肝硬化。树突状细胞（DC）是免疫系统中的主要抗原提呈细胞，并启动先天性和适应性免疫。然而，肝DC代表了一种独特的表型，其倾向于诱导耐受而不是免疫。事实上，肝DC不能启动对抗原的有效免疫是导致口服耐受和接受肝同种异体移植物而几乎没有免疫抑制的主要因素。虽然正常的肝DC诱导T细胞无反应性并且是不良的炎症引发剂，但是DC在肝纤维化状态下的功能-以及它们对纤维化过程本身的贡献-先前尚未研究。我们的初步数据表明，在肝纤维化中，肝DC在参与先天性和适应性免疫方面非常有效;此外，DC完全负责纤维化肝脏中升高的肝细胞因子环境。在肝纤维化中，肝DC增加的炎症和增强的T细胞和NK细胞的刺激取决于其升高的TNF-α的产生。基于这些观察结果，我们假设在肝纤维化状态下，肝DC功能从弱免疫原性和耐受性起始到有效诱导效应细胞免疫和炎症发生根本性转变。此外，我们推测DC功能向免疫原性的转变是肝纤维化中炎症级联反应的基础，是肝纤维化发病机制的关键组成部分。本研究的具体目的是（i）确定肝DC是否从耐受性的惰性诱导剂转化为肝纤维化中的有效免疫刺激剂，（ii）确定DC在纤维化发病机制中的贡献作用及其在HSC活化中的直接作用，（iii）确定阻断肝DC的免疫原性功能是否可以减轻对肝损伤的纤维化反应。我们预期的研究结果将表明，旨在对抗肝纤维化影响的进一步研究必须考虑DC的核心作用。我们希望我们的工作也将开辟一个新的领域，实验治疗肝纤维化的治疗。

DESCRIPTION (provided by applicant): I am a surgeon-scientist. My clinical interests are caring for patients with benign and malignant liver disease. My research interests are studying the immunological changes in acute chronic liver disease. More than 75% of my time is spent in the laboratory. My primary career goal is to become an independent investigator in liver immuno-pathology and to be able to translate my bench-work to clinical trials for my patients. My secondary goals are to inspire other young physicians to pursue investigative careers. I have a wonderful mentoring system set-up for my early career. My mentor (Alan Frey) is a leading immunologist and my co-mentor (Bruce Cronstein) is a physician who is a noted authority on the pathogenesis of chronic liver disease. I am fortunate to have a very close personal relationship with both my mentor and co-mentor. My proposed training program is enhanced by limited didactic seminar-style coursework in basic science (years 1 and 2) to enhance my understanding of molecular pathogenesis and a Masters of Science in Clinical Investigation program with a focus in Translational Medicine (years 3 and 4). The latter is a program that is directed by my co-mentor and its aim is to train clinician-scientists in the skills necessary to translate scientific discoveries to clinical settings. The research environment at NYU is extremely supportive for this work. As a highlight, we currently have a multidisciplinary liver-interest group that meets weekly to discuss clinical, basic science, and translational concepts in liver disease. My research proposal aims to study the role of liver dendritic cell activation in the pathogenesis of hepatic fibrosis. The pathogenesis of liver fibrosis is complex and our understanding of the cellular and biochemical factors underlying its development are still rudimentary. Hepatic stellate cells (HSC) are the primary producers of the extracellular matrix in liver fibrosis. After hepatic injury, a diverse interplay of cell types including immune-competent cells, such as T cells and kuppfer [sic] cells, produce an array of cytokines including IL-6, CCL21, TNF-(, and TGF-( which result in HSC activation, extracellular matrix deposition, and eventually progresses to liver fibrosis and cirrhosis. Dendritic cells (DC) are the primary antigen presenting cell in the immune system and initiate innate and adaptive immunity. However, liver DC represent a distinct phenotype that are [sic] prone to induce tolerance rather than immunity. In fact, the inability of liver DC to initiate effective immunity to antigen is a primary factor contributing to both oral tolerance and the acceptance of hepatic allografts with little immune-suppression. While normal liver DC induce T cell anergy and are poor initiators of inflammation, the function of DC in states of hepatic fibrosis - and their contribution to the fibrotic process itself - has not been previously studied. Our preliminary data show that in hepatic fibrosis, liver DC are remarkably effective at engaging both innate and adaptive immunity and; moreover, DC are entirely responsible for the elevated hepatic cytokine milieu in the fibrotic liver. The increased inflammation and enhanced stimulation of T cells and NK cells by liver DC in liver fibrosis is contingent on their elevated production of TNF-(. Based on these observations, we postulate that in states of hepatic fibrosis there is a fundamental shift in liver DC function from weak immunogenicity and initiation of tolerance to potent induction of effector cell immunity and inflammation. Furthermore, we postulate that this shift in DC function toward immunogenicity underlies the inflammatory cascade in the fibrotic liver and is a critical component to the pathogenesis of hepatic fibrosis. Specific aims of this study are (i) To determine whether liver DC convert from inert inducers of tolerance to potent immune-stimulators in liver fibrosis, (ii) To determine the contributory role of DC in the pathogenesis of fibrosis and their direct role in HSC activation, (iii) To determine whether blockade of the immunogenic function of liver DC can mitigate the fibrogenic response to liver injury. Our expected findings will suggest that further studies aimed at countering the effects of liver fibrosis must account for the central role of DC. We expect that our work will also broach a new area of experimental therapeutics in the treatment of hepatic fibrosis.