Biologic Activities of IL-36 Cytokines in Psoriasis

描述（由申请人提供）：在英国华威大学生物科学系完成博士学位后，我加入了冰岛国立大学医院免疫学系Helgi Valdimarsson教授的研究团队，在那里我接受了银屑病免疫学和遗传学的广泛培训，发表了6篇论文和2篇综述文章。随后，我加入了密歇根大学皮肤学系J.T. Elder博士的团队，作为国家牛皮癣基金会和皮肤病学基金会研究员，经过18个月的博士后指导，我被任命为研究助理教授，并作为初级教员开始了我在皮肤免疫学方面的研究生涯。我在牛皮癣免疫学方面有良好的基础，本次提案中概述的培训将使我实现以下五年的职业目标：(1)成为IL-1/IL-36生物学和牛皮癣发病机理方面的专家；(2)在大型研究机构中成为知名的、经费充足的首席研究员；(3)成为本科生、研究生和博士后层次学员的优秀导师，成功培养他们的职业发展道路。我的长期职业目标是成为一名独立的学术教师，与一个跨学科的研究团队合作，设计协作方法来解决复杂的生物医学问题。更具体地说，我希望我拓宽的知识和技能将直接转化为对牛皮癣发病机制的新见解，并确定新的治疗靶点和治疗这种疾病的方法。这个K01奖将让我沉浸在一个丰富的环境中，一个多学科的研究团队将教我生物统计学，免疫学和分子生物学技能，以实现我的职业目标。研究环境：我拥有成功完成这个项目所需的所有资源，包括400平方米。一英尺的实验室空间配有设备

DESCRIPTION (provided by applicant): After completing my Ph.D. in the Department of Biological Sciences, University of Warwick, UK, I joined the research team of Prof. Helgi Valdimarsson in the Department of Immunology at the National University Hospital, Iceland, where I gained extensive training in psoriasis immunology and genetics, generating 6 publications and 2 review articles. I subsequently joined Dr. J.T. Elder's team in the Department of Dermatology at the University of Michigan, and after 18 months' post-doctoral mentoring as a National Psoriasis Foundation and Dermatology Foundation Fellow, I was appointed Research Assistant Professor, and as junior faculty have set about establishing my research career in skin immunology. I have a sound foundation in psoriasis immunology and the training outlined in this proposal will allow me to achieve these five-year career goals: (1) To become an expert in IL-1/IL-36 biology and psoriasis pathogenesis; (2) To become an established, well-funded principal investigator at a major research institution; (3) Be an excellent mentor to undergraduate, graduate and post-doctoral level trainees and successfully foster their career paths. My long- term career goal is to be an independent academic faculty member, working with an interdisciplinary research team to devise collaborative approaches to solve complex biomedical problems. More specifically, I anticipate that my broadened knowledge and skill sets will directly translate into new insights into the pathogenesis of psoriasis and the identification of novel therapeutic targets and approaches to treating this disease. This K01 award will allow me to become immersed in a rich environment where a multidisciplinary team of investigators will teach me the biostatistics, immunology and molecular biological skills needed to achieve my career goals. Research Environment: I have at my disposal all of the resources required to successfully complete this project, including 400 sq. ft. of lab space furnished with equipment for cell culture, RNA isolation, PCR, flow cytometry. I have the mentorship of Dr. Elder and an Advisory Committee composed of prominent experts in biostatistics (Dr. Goncalo Abecasis), T cell biology (Dr. Weiping Zou), IL-1/inflammasome biology (Dr. Gabriel Nunez) and dermatology (Dr. John Voorhees). Under the supervision of my mentors, a comprehensive training plan has been devised for my career development: (1) To develop skills in statistics and systems biology analysis - a number of formal courses/workshops have been targeted together with the guidance of Drs. Abecasis and Elder. (2) To develop knowledge and skills in keratinocyte biology and function - mentoring from Dr. Elder and a formal course and collaboration with the Skin Disease Resource Center Keratinocyte Core facility, Northwestern University. (3) To develop knowledge and skills to study the skin immune system and T cell biology - mentoring by Dr. Zou and formal training with the Flow Cytometry Core Facility, University of Michigan. (4) To hone grant writing skills and learn to write effective internal review board (IRB) proposals for ethically conducted research on human subjects including the responsible conduct of research (RCR) - I will use of a number of resources at University of Michigan to develop skills for grantsmanship, IRB proposals, and training in RCR issues. (5) To foster leadership, mentoring and team-building skills - this will be achieved by working closely with rotating undergraduate and graduate students and students in the University of Michigan Undergraduate Research Opportunity Program where I will be able to recruit and work with an undergraduate student on a multiple year basis to foster their scientific development and interest in medical research. (6) To improve written and oral communication skills - through attending both Dermatology and Immunology departmental research meetings as well as participating in national immunology and dermatology meetings. Research Project: Psoriasis is an inflammatory and hyperproliferative skin disease driven by interactions of T cell, antigen-presenting cells (APC), keratinocytes and cytokines. The IL-36 cytokines (IL-36¿, ¿, ? and IL-36Ra) are recently defined members of the IL-1 family and are overexpressed in lesional psoriasis tissue. The broad, long-term objective of this proposal is to understand how the expression, processing and function of IL- 36 cytokines impact on the epidermal hyperplasia seen in psoriasis and identify opportunities for the development of innovative therapeutic strategies. Our central hypothesis is that IL-36 cytokines contribute to psoriatic inflammation by (a) directly driving keratinocyte innate host defense in an autocrine manner, and (b) activating APC to invoke Th17 T cell responses which then (c) synergize with IL-36 in amplifying the keratinocyte response. There are a number of uncharacterized steps regulating the secretion of active IL-36 from keratinocytes and the effects of IL-36 on human APC and KC remain to be elucidated. To test this hypothesis, we set out the following Specific Aims: (1) Determine whether IL-36 proteolysis occurs in KC and delineate the mechanism of IL-36 secretion; (2) Determine the differences in the activity of IL-36¿, ¿ and ? and their contribution to skin inflammation; (3) Elucidate the role of IL-36 on APC function and the Th1/Th17 T cell bias in psoriasis.