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.
Systemic Lupus Erythematosus is a devastating autoimmune disease that affects up to 0.5% of the US population. It results in severe organ damage, elevated risk of cardiovascular disease, and disfiguring scars. Current therapies are globally immunosuppressive and cause significant morbidity. In order to improve patient care and create better treatments, an improved understanding of the mechanisms that drive lupus development is required. This proposal strives to create a pathway by which the candidate can develop an integrated knowledge of the mechanisms of systemic and cutaneous lupus and begin to dissect the role of the inflammasome and innate immunity in this disease. The results of this work will provide novel targets for treatment development and lead to improved patient care and outcomes.
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