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Kallikrein-PAR interactions in skin inflammation

激肽释放酶-PAR 在皮肤炎症中的相互作用

基本信息

批准号：
10208722
负责人：
Nicole Leanne Ward
金额：
$ 25.54万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208722
关键词：
Acanthosis Address Adverse reactions Affect Atopic Dermatitis Attenuated Autoimmunity Backcrossings Biological Bone Marrow CRISPR/Cas technology Cells Cleaved cell Coculture Techniques Coupled Cutaneous Data Set Disease remission Environment F2R gene FDA approved Genetic Genetically Engineered Mouse Hematopoietic Histologic Human Hyperactivity Immune In Vitro Infiltration Inflammation Interleukin-17 Kininogenase Knock-out Knockout Mice Lesion Measures Mediating Messenger RNA Modeling Molecular Molecular Genetics Mus Organ Culture Techniques Organ Transplantation PAR-1 Receptor Pathogenesis Pathogenicity Pathway interactions Patients Peptide Hydrolases Phenotype Population Prevalence Proteinase-Activated Receptors Proteins Psoriasiform Dermatitis Psoriasis Publishing Research Resistance Rho-associated kinase Role Serine Protease Severities Severity of illness Signal Pathway Signal Transduction Skin Small Interfering RNA T-Lymphocyte Testing Therapeutic Time Transcript Translating Tumor-infiltrating immune cells Work Xenograft Model Xenograft procedure chronic inflammatory disease cytokine experimental study improved in vivo inhibitor/antagonist innovation interleukin-23 mouse model new therapeutic target novel overexpression prevent receptor recombinase-mediated cassette exchange reduce symptoms skin lesion small molecule therapeutic development therapeutically effective transcriptome sequencing whole genome

项目摘要

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation and autoimmunity via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 is expressed in skin, however its biological activities in vivo remain largely unknown. Recent work published by our lab identified increases in KLK6 mRNA and protein in psoriasis patient lesional skin and primary KCs that decrease rapidly with treatment and correspond with disease severity. Despite KLK6 being a highly regulated cutaneous transcript/protein, the pathogenic significance of KLK6 in psoriasis remains unknown. To address this question, we genetically engineered mice to overexpress KLK6 in KCs (modeling lesional psoriasis skin). KLK6+ mice spontaneously develop a psoriasiform skin phenotype at the histological, cellular and molecular levels and RNAseq analyses of KLK6+ mouse skin revealed high correspondence with human psoriasis and identified significant increases in T cell derived-cytokines Il22 and Il17a/f. To identify the mechanisms mediating KLK6-elicited inflammation, KLK6+ mice were backcrossed with either PAR1- or PAR2-deficient (KO) mice. KLK6+PAR2KO mice develop similar levels of skin inflammation as KLK6+ mice. In contrast, KLK6+PAR1KO mice have attenuated skin inflammation demonstrating a critical pathogenic role for PAR1, and not PAR2 in KLK6-induced skin inflammation. PAR1 is found on KCs and T cells and signals through Rac1 and Rho associated kinase (ROCK)2. Using this innovative new mouse model, combined with genetic knockout approaches, cre-lox technologies and small molecule inhibition targeting strategies coupled with in vitro co-culture, CRISPR-Cas9 and cell signaling approaches, we will test the hypothesis that KLK6 cleaves PAR1 on KCs and T cells and activates Rac1 and ROCK2, initiating a self-sustaining proinflammatory loop between KCs and T cells that results in a psoriasis-like proinflammatory environment. Ultimately, we will show using human psoriasis skin organ cultures and xenograft models that interfering with new targets in this pathway will improve human psoriasis. The work proposed herein will identify the cellular mechanism(s) underlying KLK6-PAR1-mediated inflammation. Successful completion of our aims will identify KLK6 as a critical protease for psoriasis pathogenesis and KLK6-PAR1 signaling as a new target for therapy. This pathway is profoundly different than currently targeted cytokine pathways being investigated for the treatment of chronic inflammatory disease and offers a new direction in psoriasis research and autoimmunity research as a whole.

klikrein相关肽酶6 （KLK6）是一种分泌丝氨酸蛋白酶，据推测可促进炎症