Biologic Activities of IL-36 Cytokines in Psoriasis

IL-36 细胞因子在银屑病中的生物活性

• 批准号: 9325432
• 负责人: Andrew Johnston
• 金额: $ 10.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325432
• 关键词: Advisory Committees; Affect; American; Antigen-Presenting Cells; Antigens; Automobile Driving; Bioinformatics; Biological; Biological Sciences; Biology; Biometry; Biopsy; Blood; Career Choice; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Chronic; Chronic small plaque psoriasis; Collaborations; Complex; Core Facility; Data; Dendritic Cells; Dermatologic; Dermatology; Development; Disease; Doctor of Philosophy; Educational workshop; Elderly; Environment; Epithelial; Equipment; Ethics; Faculty; Family; Family member; Flow Cytometry; Fostering; Foundations; Funding; Gene Expression Profile; Genetic; Goals; Grant; Guide RNA; Host Defense; Human; Hyperplasia; Iceland; Immune response; Immune system; Immunology; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Institution; Interdisciplinary Study; Interleukin-1; Interleukins; Knowledge; Langerhans cell; Lead; Leadership; Learning; Length; Lesion; Leukocytes; Mass Spectrum Analysis; Medical Research; Mentored Research Scientist Development Award; Mentors; Mentorship; Messenger RNA; Michigan; Mixed Lymphocyte Culture Test; Molecular; Myelogenous; N-terminal; Pathogenesis; Patients; Pattern; Pharmacology; Phenotype; Postdoctoral Fellow; Principal Investigator; Process; Production; Proteolysis; Proteomics; Psoriasis; Publications; Pustular psoriasis; RNA; Receptor Signaling; Recombinants; Recruitment Activity; Research; Research Assistant; Research Personnel; Research Project Grants; Resolution; Resources; Role; Signal Transduction; Signaling Molecule; Skin; Superantigens; Supervision; Systems Biology; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Translating; Universities; University Hospitals; Viral Tumor Antigens; Work; Writing; autocrine; career; career development; collaborative approach; cost; cytokine; extracellular; genetic manipulation; graduate student; human subject; improved; innovation; insight; interest; keratinocyte; loss of function mutation; meetings; member; monocyte; monolayer; mouse model; multidisciplinary; new therapeutic target; novel; oral communication; overexpression; pathogen; professor; programs; public health relevance; reconstitution; response; responsible research conduct; skills; skin disorder; sound; square foot; statistics; transcriptome sequencing; undergraduate research; undergraduate student

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-36α, ß, γ 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-36α, ß, γ 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.

描述（由申请人提供）：完成博士学位后。在英国华威大学生物科学系学习期间，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，在那里我获得了银屑病免疫学和遗传学方面的广泛培训，发表了 6 篇出版物和 2 篇评论文章。随后我加入了 J.T. 博士。在密歇根大学皮肤病学系的埃尔德团队的帮助下，经过 18 个月的国家银屑病基金会和皮肤病学基金会研究员的博士后指导，我被任命为研究助理教授，作为初级教师，我开始在皮肤免疫学领域建立我的研究生涯。我在银屑病免疫学方面有良好的基础，本提案中概述的培训将使我能够实现以下五年职业目标： (1) 成为 IL-1/IL-36 生物学和银屑病发病机制的专家； (2) 成为主要研究机构的资深、资金充足的首席研究员； （3）成为本科生、研究生和博士后的优秀导师，成功培育他们的职业道路。我的长期职业目标是成为一名独立的学术教员，与跨学科研究团队合作，设计协作方法来解决复杂的生物医学问题。更具体地说，我预计我扩大的知识和技能将直接转化为对银屑病发病机制的新见解以及治疗这种疾病的新治疗靶点和方法的确定。这个 K01 奖项将使我沉浸在一个丰富的环境中，多学科研究团队将教我实现职业目标所需的生物统计学、免疫学和分子生物学技能。研究环境：我拥有成功完成该项目所需的所有资源，包括 400 平方英尺的实验室空间，配备了用于 细胞培养、RNA分离、PCR、流式细胞术。我得到了 Elder 博士的指导，以及由生物统计学（Goncalo Abecasis 博士）、T 细胞生物学（邹卫平博士）、IL-1/炎性体生物学（Gabriel Nunez 博士）和皮肤病学（John Voorhees 博士）等领域的著名专家组成的咨询委员会。在我的导师的监督下，为我的职业发展制定了全面的培训计划：（1）培养统计和系统生物学分析技能 - 在博士的指导下，我们开设了许多正式课程/研讨会。阿贝卡西斯和埃尔德。 (2) 发展角质形成细胞生物学和功能方面的知识和技能 - 埃尔德博士的指导以及正式课程以及与西北大学皮肤病资源中心角质形成细胞核心设施的合作。 (3) 培养研究皮肤免疫系统和 T 细胞生物学的知识和技能 - 由 Zou 博士指导并接受密歇根大学流式细胞术核心设施的正式培训。 (4) 磨练拨款写作技巧并学习编写有效的内部审查委员会 (IRB) 提案，以道德地进行人类受试者研究，包括负责任的研究行为 (RCR) - 我将利用密歇根大学的大量资源来培养拨款、IRB 提案和 RCR 问题培训的技能。 (5) 培养领导力、指导和团队建设技能——这将通过与轮流本科生和研究生以及密歇根大学本科生研究机会计划的学生密切合作来实现，在该计划中，我将能够招募本科生并与他们一起工作多年，以促进他们的科学发展和对医学研究的兴趣。 (6) 提高书面和口头沟通技巧 - 通过参加皮肤病学和免疫学部门研究会议以及参加国家免疫学和皮肤病学会议。研究项目：牛皮癣是一种炎症性和过度增殖性皮肤病，由 T 细胞、抗原呈递细胞 (APC)、角质形成细胞和细胞因子的相互作用驱动。 IL-36 细胞因子（IL-36α、β、γ 和 IL-36Ra）是最近确定的 IL-1 家族成员，在皮损银屑病组织中过度表达。该提案的广泛、长期目标是了解 IL-的表达、加工和功能如何 36 种细胞因子对牛皮癣中表皮增生的影响并确定治疗的机会 开发创新的治疗策略。我们的中心假设是，IL-36 细胞因子通过 (a) 直接驱动角化细胞先天宿主防御而导致银屑病炎症。 (b) 激活 APC 以引发 Th17 T 细胞反应，然后 (c) 与 IL-36 协同作用，放大角质形成细胞反应。有许多未表征的步骤调节角质形成细胞分泌活性 IL-36，并且 IL-36 对人 APC 和 KC 的影响仍有待阐明。为了验证这一假设，我们提出了以下具体目标：（1）确定KC中是否发生IL-36蛋白水解，并描述IL-36分泌的机制； (2)确定IL-36α、β、γ活性的差异及其对皮肤炎症的贡献； (3)阐明IL-36对银屑病APC功能和Th1/Th17 T细胞偏向的作用。

项目成果

In the Red: Deficits in Immune Regulation Underlie Psoriasis Severity.

红色：免疫调节缺陷是银屑病严重程度的基础。

• DOI: 10.1016/j.jid.2016.08.008
• 发表时间: 2016
• 期刊: The Journal of investigative dermatology
• 作者: Johnston,Andrew

Resolving Inflammation by Targeting an Ancient Innate Immune Sensor with a Bacterial Metabolite.

通过用细菌代谢物靶向古老的先天免疫传感器来解决炎症。

• DOI: 10.1016/j.jid.2017.07.815
• 发表时间: 2017
• 期刊: The Journal of investigative dermatology
• 作者: Johnston,Andrew

Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis.

• DOI: 10.2340/00015555-2408
• 发表时间: 2016-08-23
• 期刊: Acta dermato-venereologica
• 影响因子: 3.6
• 作者: Thorleifsdottir RH;Eysteinsdóttir JH;Olafsson JH;Sigurdsson MI;Johnston A;Valdimarsson H;Sigurgeirsson B
• 通讯作者: Sigurgeirsson B