The Role of Innate Immunity in Systemic and Cutaneous Lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）的皮肤和全身表现往往是孤立的，因此皮肤病理学对系统性疾病发展的影响往往被忽视和研究不足。该申请提出了一个职业发展和研究计划，以促进我对皮肤和系统性自身免疫性疾病之间关系的理解，从而为我提供了一个研究SLE和其他潜在自身免疫性疾病的利基。候选人/职业发展计划：在整个培训过程中，我通过不断整合研究和临床知识，证明了我对学术医学事业的承诺，我在地方和国家层面都获得了卓越的认可。在这个时刻，我准备在学术医学的职业生涯，我建议这个奖项将促进实现我的长期职业目标所需的培训：1。成为系统性和皮肤病狼疮发病机制的专家，特别是先天免疫系统如何在疾病发展中发挥作用。2.成为一个建立，资金充足的首席研究员和终身教授在一个主要的医学研究机构。3.成为本科生，研究生和博士后水平的学员的优秀导师，并成功地培养他们的职业道路。为了实现这些长期目标，我需要在特定的科学和职业发展领域的培训，这将通过正式的课程工作，研讨会和导师及其实验室的实践培训相结合来实现。我建议学习的科学技能包括系统生物学分析的应用;疾病小鼠模型的操作和表征;以及理解皮肤免疫学所需的技术。此外，我的职业发展目标：学会写有效的内部审查委员会建议，对人类受试者进行道德研究;培养领导能力，指导和团队建设技能;提高书面和口头沟通技巧将在拟议的赠款期间得到解决和实现。环境：目前，我是密歇根大学的初级教师，在Mariana Kaplan博士的实验室工作。我建议通过这笔赠款扩大我的导师圈子，包括系统生物学和皮肤病模型的国际专家。因此，我不仅可以通过我目前的实验室充分使用最先进的设施和设备，而且我将在其他运行良好、资金充足的实验室中获得实践培训和指导，这些实验室培养了许多成功的医生科学家。此外，内科和流变学部门将保护我的研究时间，并为我提供充足的空间和启动资金，以支持我的职业生涯和实验室发展。研究：提出的科学目标将促进我的职业发展目标，以及追求的假设，角质形成细胞是一个重要来源的局部和全身IL-18水平在SLE患者和IL-18的生产是增加暴露于I型干扰素（IFN），并有助于皮肤炎症和全身器官损伤。为了更好地理解I型IFN对角质形成细胞炎性体活化的调节的影响，AIM 1将检查I型IFN对角质形成细胞中炎性体的表达和活化的影响。IL-18已被证明是由角质形成细胞产生的，并可能在调节角质形成细胞功能中发挥重要作用，因此AIM 2将使用系统生物学方法来了解IL-18对角质形成细胞的影响以及I型IFN的存在如何调节这种影响。为了理解IL-18在皮肤狼疮的体内模型中的作用，AIM 3将评估有和没有IL-18阻断的狼疮易感小鼠的胶带剥离。将监测持续性狼疮样皮疹的发展、炎性浸润成分和全身性疾病发展的加速。

DESCRIPTION (provided by applicant): The cutaneous and systemic manifestations of systemic lupus erythematosus (SLE) are often approached in isolation, thus the influence of cutaneous pathology on systemic disease development is often overlooked and under-researched. This application proposes a career development and research plan to facilitate my understanding of the relationship between the skin and systemic autoimmune disease, thus providing me with a niche from which to study SLE and potentially other autoimmune diseases. Candidate/Career Development Plan: I have demonstrated my commitment to a career in academic medicine throughout my training by continually integrating research and clinical knowledge, and I have been recognized at the local and national level for excellence in both. At this juncture, I am poised for a career in academic medicine and I propose that this award will facilitate the training required to achieve my long-term career goals: 1. Become an expert in systemic and dermatologic lupus pathogenesis, particularly in how the innate immune system plays a role in disease development. 2. Become an established, well-funded principal investigator and tenured professor at a major medical research institution. 3. Be an excellent mentor to undergraduate, graduate and post-doctoral level trainees and successfully foster their career paths. In order to achieve these long term goals, I require training in specific scientific and career-development arenas, which will be achieved through a combination of formal course work, seminars and hands-on training from mentors and their labs. The scientific skills I propose to learn include application of systems biology analysis; manipulation and characterization of mouse models of disease; and techniques required for understanding dermatologic immunology. Additionally, my career development goals: learning to write effective internal review board proposals for ethically conducted research on human subjects; fostering leadership, mentoring and team building skills; and improving written and oral communication skills will be addressed and achieved during the proposed grant period. Environment: Currently, I am junior faculty at the University of Michigan and work in the lab of Dr. Mariana Kaplan. I am proposing to expand my mentorship circle through this grant to include international experts in systems biology as well as dermatologic models of disease. Thus, not only do I have ample access to state-of- the-art facilities and equipment through my current lab, but I will have hands-on training and mentorship in other well-run and well-funded laboratories that have trained many successful physician scientists. Additionally, the Department of Internal Medicine and Divison of Rheumatology will protect my time for research and provide me with ample space and start-up funds to support my career and lab development. Research: The proposed scientific aims will foster my career development goals as well as pursue the hypothesis that keratinocytes are an important source of both local and systemic IL-18 levels in SLE patients and this IL-18 production is increased by exposure to type I interferons (IFNs) and contributes to both skin inflammation and systemic organ damage. In order to better understand the impact of type I IFNs on modulation of keratinocyte inflammasome activation, AIM 1 will examine the influence of type I IFNs in the expression and activation of the inflammasome in keratinocytes. IL-18 has been shown to be produced by keratinocytes and may have an important role in modulating keratinocyte function, so AIM 2 will use a systems biology approach to understand the impact of IL-18 on keratinocytes and how this is modulated by the presence of type I IFNs. In order to understand the role of IL-18 in an in vivo model of cutaneous lupus, AIM3 will evaluate tape stripping of lupus prone mice with and without IL-18 blockade. Development of a persistent lupus-like rash, inflammatory infiltrate composition and acceleration of systemic disease development will be monitored.