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:
  • 金额:
    $ 25.54万
  • 依托单位:
  • 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

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

项目成果

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Nicole Leanne Ward其他文献

Nicole Leanne Ward的其他文献

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{{ truncateString('Nicole Leanne Ward', 18)}}的其他基金

Kallikrein-PAR interactions in skin inflammation
激肽释放酶-PAR 在皮肤炎症中的相互作用
  • 批准号:
    10615327
  • 财政年份:
    2018
  • 资助金额:
    $ 25.54万
  • 项目类别:
Kallikrein-PAR interactions in skin inflammation
激肽释放酶-PAR 在皮肤炎症中的相互作用
  • 批准号:
    10449979
  • 财政年份:
    2018
  • 资助金额:
    $ 25.54万
  • 项目类别:
Core 1: Pre-clinical Modeling Core
核心 1:临床前建模核心
  • 批准号:
    10005123
  • 财政年份:
    2017
  • 资助金额:
    $ 25.54万
  • 项目类别:
Project 1: Host Immune Response to Chronic Psoriasis Inflammation
项目 1:宿主对慢性银屑病炎症的免疫反应
  • 批准号:
    10259876
  • 财政年份:
    2017
  • 资助金额:
    $ 25.54万
  • 项目类别:
Core 1: Pre-clinical Modeling Core
核心 1:临床前建模核心
  • 批准号:
    10259874
  • 财政年份:
    2017
  • 资助金额:
    $ 25.54万
  • 项目类别:
Project 1: Host Immune Response to Chronic Psoriasis Inflammation
项目 1:宿主对慢性银屑病炎症的免疫反应
  • 批准号:
    10005125
  • 财政年份:
    2017
  • 资助金额:
    $ 25.54万
  • 项目类别:
IL-17C mediated mechanisms of inflammation
IL-17C 介导的炎症机制
  • 批准号:
    8445590
  • 财政年份:
    2013
  • 资助金额:
    $ 25.54万
  • 项目类别:
Neurogenic inflammation and psoriasiform dermatitis
神经源性炎症和牛皮癣样皮炎
  • 批准号:
    8706044
  • 财政年份:
    2013
  • 资助金额:
    $ 25.54万
  • 项目类别:
IL-17C mediated mechanisms of inflammation
IL-17C 介导的炎症机制
  • 批准号:
    8636995
  • 财政年份:
    2013
  • 资助金额:
    $ 25.54万
  • 项目类别:
IL-17C mediated mechanisms of inflammation
IL-17C 介导的炎症机制
  • 批准号:
    9039538
  • 财政年份:
    2013
  • 资助金额:
    $ 25.54万
  • 项目类别:

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