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，因此皮肤病理对全身性疾病发展的影响往往被忽视和研究不足。这份申请提出了一个职业发展和研究计划，帮助我了解皮肤与全身性自身免疫性疾病之间的关系，从而为我提供一个研究SLE以及潜在的其他自身免疫性疾病的利基。候选人/职业发展计划：通过不断整合研究和临床知识，在整个培训过程中，我已经证明了我对学术医学事业的承诺，并且我在地方和国家层面都获得了卓越的认可。在这个关键时刻，我准备在学术医学领域的职业生涯，我建议这个奖项将有助于实现我的长期职业目标所需的培训：成为系统性和皮肤性狼疮发病机制方面的专家，特别是先天免疫系统在疾病发展中的作用。2. 成为一家大型医学研究机构的知名、资金充足的首席研究员和终身教授。3. 成为本科生、研究生和博士后学员的优秀导师，成功培养他们的职业发展道路。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进行培训，这将通过正式的课程学习、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，我的职业发展目标是：学习为合乎伦理的人类研究撰写有效的内部审查委员会提案；培养领导、辅导和团队建设技能；提高书面和口头沟通技巧将在拟议赠款期间得到处理和实现。环境：目前，我是密歇根大学的初级教员，在Mariana Kaplan博士的实验室工作。我建议通过这笔资助扩大我的指导圈子，包括系统生物学和皮肤病模型方面的国际专家。因此，我不仅可以通过目前的实验室充分利用最先进的设施和设备，而且还可以在其他管理良好、资金充足的实验室接受实践培训和指导，这些实验室培养了许多成功的内科科学家。此外，内科和风湿病科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，并追求角化细胞是SLE患者局部和全身IL-18水平的重要来源，这种IL-18的产生通过暴露于I型干扰素（ifn）而增加，并有助于皮肤炎症和全身器官损伤的假设。为了更好地了解I型ifn对角化细胞炎症小体活化的调节作用，AIM 1将研究I型ifn对角化细胞炎症小体表达和活化的影响。IL-18已被证明是由角质形成细胞产生的，并且可能在调节角质形成细胞的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。为了了解IL-18在皮肤狼疮体内模型中的作用，AIM3将评估有和没有IL-18阻断的狼疮易感小鼠的胶带剥离。持续红斑狼疮样皮疹的发展，炎症浸润成分和全身性疾病发展的加速将被监测。

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.