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.

Public Health Relevance

Psoriasis is a common, chronic and often debilitating skin disease affecting over 4 million Americans at an estimated cost in excess of $11.25 billion annually. Psoriasis occurs when white blood cells infiltrate the skin causing severe inflammation in processes controlled by cell signaling molecules, several of which, known as the IL-36 family, have recently been discovered and are abundantly expressed in psoriasis skin. We will investigate the role of these new molecules on the activation of white blood cells and the profound skin inflammation seen in psoriasis with the ultimate goal of identifying novel treatments for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR064765-02
Application #
8699143
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Thorleifsdottir, Ragna H; Sigurdardottir, Sigrun L; Sigurgeirsson, Bardur et al. (2016) HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series. J Am Acad Dermatol 75:889-896
Fritz, Yi; Klenotic, Philip A; Swindell, William R et al. (2016) Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice. J Invest Dermatol :
Xing, Xianying; Liang, Yun; Sarkar, Mrinal K et al. (2016) IL-17 Responses Are the Dominant Inflammatory Signal Linking Inverse, Erythrodermic, and Chronic Plaque Psoriasis. J Invest Dermatol 136:2498-2501
Johnston, Andrew (2016) Interleukin-29: Just an extra string in the bow of Th17 cells or a target for therapeutic exploitation? J Mol Med (Berl) 94:373-6
Thorleifsdottir, Ragna H; Eysteinsdóttir, Jenna H; Olafsson, Jón H et al. (2016) Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis. Acta Derm Venereol 96:788-91
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Stoll, Stefan W; Stuart, Philip E; Lambert, Sylviane et al. (2016) Membrane-Tethered Intracellular Domain of Amphiregulin Promotes Keratinocyte Proliferation. J Invest Dermatol 136:444-52
Johnston, A; Yin, Z; Gudjonsson, J E (2016) Still waters run deep: latent cytokine activity in nonlesional psoriasis skin. Br J Dermatol 174:19-20
Ward, Nicole L; Bhagathavula, Narasimharao; Johnston, Andrew et al. (2015) Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture. J Invest Dermatol 135:910-3
Lundberg, Kathleen C; Fritz, Yi; Johnston, Andrew et al. (2015) Proteomics of skin proteins in psoriasis: from discovery and verification in a mouse model to confirmation in humans. Mol Cell Proteomics 14:109-19

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