The Role of Innate Immunity in Systemic and Cutaneous Lupus

描述(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，因此皮肤病理对系统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，以促进我对皮肤和系统性自身免疫性疾病之间的关系的理解，从而为我提供了一个研究SLE和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，我在整个培训过程中展示了我对学术医学职业生涯的承诺，我在这两方面都表现出色，在地方和国家层面都得到了认可。此时此刻，我准备从事学术医学，我建议这个奖项将促进实现我长期职业目标所需的培训：1.成为系统性和皮肤病发病机制方面的专家，特别是在先天性免疫系统如何在疾病发展中发挥作用方面。2.成为一家大型医学研究机构的知名、资金雄厚的首席研究员和终身教授。3.当好本科生、研究生和博士后学员的良师益友，成功培育他们的职业道路。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进行培训，这将通过正规课程工作、研讨会和导师及其实验室的实践培训相结合的方式实现。我打算学习的科学技能包括系统生物学分析的应用；小鼠疾病模型的操作和表征；以及理解皮肤病免疫学所需的技术。此外，我的职业发展目标：学习撰写有效的内部审查委员会关于以道德方式进行的关于人类主题的研究的建议；培养领导力、指导和团队建设技能；以及提高书面和口头沟通技能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员，在玛丽安娜·卡普兰博士的实验室工作。我建议通过这笔赠款扩大我的导师圈，将系统生物学和皮肤病模型方面的国际专家包括在内。因此，通过我目前的实验室，我不仅有足够的机会接触到最先进的设施和设备，而且我还将在其他运营良好、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：拟议的科学目标将促进我的职业发展目标，并追求这样的假设，即角质形成细胞是SLE患者局部和全身IL-18水平的重要来源，这种IL-18的产生因暴露于I型干扰素(IFN)而增加，并导致皮肤炎症和全身器官损伤。为了更好地了解I型IFN对角质形成细胞炎性小体激活的调控作用，AIM 1将检测I型IFN对角质形成细胞中炎性小体表达和激活的影响。IL-18已被证明由角质形成细胞产生，并可能在角质形成细胞的功能调节中起重要作用，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的存在是如何调节这种影响的。为了了解IL-18在皮肤狼疮活体模型中的作用，AIM3将评估使用和不使用IL-18阻断的狼疮易感小鼠的磁带剥离。将监测持续性狼疮样皮疹、炎性浸润物成分的发展以及全身性疾病的加速发展。

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.