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Project Summary Pulmonary fibrosis (PF) remains a major and growing medical burden with unsatisfactory therapeutic options that fail to reverse established disease. Our prior work has identified that YAP/TAZ activation in fibroblasts is a central feature of the pathological feedback loop that propagates progression of PF. In the prior funding cycle, we identified Dopamine D1 receptor (D1R) agonism as a strategy to inactivate YAP/TAZ selectively in lung fibroblasts, leading to accelerated resolution of experimental pulmonary fibrosis in mice in part by switching lung fibroblasts from matrix depositing to matrix degrading state. Moreover, we demonstrated that the lungs of individuals with PF exhibit a deficit in expression of DOPA decarboxylase (DDC), the enzyme that catalyzes conversion of L-DOPA into bioactive dopamine. These studies lead us to propose that restoration of endogenous local dopamine levels in the lung is an essential trigger for the matrix degradation and fibrosis clearance that is essential to successful repair of the lung, but is impaired in PF. Our preliminary data show that Ddc transcripts are transiently depressed in lung tissue of young mice following bleomycin injury and rise during fibrosis resolution, whereas aged mice exhibited sustained reductions in Ddc that parallel persistent fibrosis. Moreover, small molecule inhibition of Ddc enzymatic activity or the D1R from day 21 to 42 post- bleomycin in young mice ablates the spontaneous resolution of lung fibrosis, demonstrating the essential role for dopamine signaling in fibrosis resolution. In addition, we find that dopamine is detectable in supernatants of precision cut lung slices and is diminished in slices cultured from fibrotic lungs, confirming the local synthesis of dopamine within the lung. Based on these findings, we propose to test the central hypothesis that epithelial dopamine synthesis is essential to fibrosis resolution and that restoration of normal dopamine levels in PF lung tissue can promote collagen resorption and repair of the lung. We will test this hypothesis in three aims spanning non-resolving mouse models of pulmonary fibrosis as well as ex vivo models of mouse and human lung tissues. To define the functional roles of dopamine signaling we will leverage both cell-specific conditional genetic models as well as well-characterized small molecule inhibitors and dopamine agonists in these systems. Together our studies will define the cellular sources and regulatory systems that control dopamine bioavailability during normal lung repair, and will delineate how this repair system fails in human PF. These studies may reveal new therapeutic approaches to promote fibrosis resolution and lung repair.
期刊论文(28)
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DOI: 10.1371/journal.pone.0019929
发表时间: 2011
期刊: PloS one
影响因子: 3.7
作者: [Mih JD, Sharif AS, Liu F, Marinkovic A, Symer MM, Tschumperlin DJ]
通讯作者: Tschumperlin DJ
DOI: 10.1002/jcp.30459
发表时间: 2021-11
期刊: Journal of cellular physiology
影响因子: 5.6
作者: [Choi KM, Haak AJ, Diaz Espinosa AM, Cummins KA, Link PA, Aravamudhan A, Wood DK, Tschumperlin DJ]
通讯作者: Tschumperlin DJ
DOI: 10.1111/j.1524-475x.2010.00655.x
发表时间: 2011-03
期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
影响因子: --
作者: [Shiomi T, Boudreault F, Padem N, Higashiyama S, Drazen JM, Tschumperlin DJ]
通讯作者: Tschumperlin DJ
DOI: 10.1513/annalsats.201407-320mg
发表时间: 2015-04
期刊: Annals of the American Thoracic Society
影响因子: 8.3
作者: [D. Tschumperlin]
通讯作者: D. Tschumperlin
12
    Fibrogenic activation and memory in the lung mesenchyme
    • 批准号:
      10558822
    • 项目类别:
    • 资助金额:
      $59.6万
    • 财政年份:
      2022
    • 负责人:
      Daniel J. Tschumperlin
    • 依托单位:
    2021 Lung Development, Injury and Repair Gordon Research Conference and Gordon Research Seminar
    • 批准号:
      10217714
    • 项目类别:
    • 资助金额:
      $1.0万
    • 财政年份:
      2021
    • 负责人:
      Daniel J. Tschumperlin
    • 依托单位:
    Therapeutic ECM Resorption in Cellular Systems and Precision Cut Lung Slices.
    • 批准号:
      10530660
    • 项目类别:
    • 资助金额:
      $63.32万
    • 财政年份:
      2020
    • 负责人:
      Daniel J. Tschumperlin
    • 依托单位:
    Therapeutic ECM Resorption in Cellular Systems and Precision Cut Lung Slices.
    • 批准号:
      10318078
    • 项目类别:
    • 资助金额:
      $61.97万
    • 财政年份:
      2020
    • 负责人:
      Daniel J. Tschumperlin
    • 依托单位:
    海外基金