Elucidating fibroblast heterogeneity as a pathway to target organ fibrosis

Information

  • Research Project
  • 10272408
  • ApplicationId
    10272408
  • Core Project Number
    R01GM118300
  • Full Project Number
    7R01GM118300-05
  • Serial Number
    118300
  • FOA Number
    PA-18-590
  • Sub Project Id
  • Project Start Date
    6/3/2016 - 8 years ago
  • Project End Date
    3/31/2021 - 3 years ago
  • Program Officer Name
    GARCIA, MARTHA
  • Budget Start Date
    9/1/2020 - 4 years ago
  • Budget End Date
    3/31/2021 - 3 years ago
  • Fiscal Year
    2019
  • Support Year
    05
  • Suffix
  • Award Notice Date
    11/27/2020 - 4 years ago

Elucidating fibroblast heterogeneity as a pathway to target organ fibrosis

PROJECT SUMMARY Following surgical or traumatic injury, organs and tissues can heal by regeneration but more often than not, the repair process is complicated by fibrosis, resulting in reduced function and eventually organ failure. Activated fibroblasts (FBs) are the central mediators of both repair and fibrosis making it difficult to target fibrosis without affecting repair. It is now well accepted that FBs represent a heterogeneous population of cells, yet we have a poor understanding of the molecular, cellular and functional basis of this heterogeneity. Our preliminary data have identified two major and distinct activated FB populations in mouse heart, skin and kidney following injury: Fibroblast specific protein 1 (FSP1)-expressing FBs and ?-smooth muscle actin (?SMA)-expressing FBs, which appear at different time points after injury and remained as discrete populations during the healing process. Using mice which express GFP under FSP1 or ?-SMA promoters we isolated these activated FB populations post cardiac injury and compared the gene expression profile of each population to those of FBs isolated from the uninjured heart. RNA sequencing indicated distinct molecular signatures. Particularly, pro-fibrotic genes such as type I collagen (Col I) and TGF? signaling were significantly upregulated in ?SMA-FBs, whereas genes involved in cellular homeostasis, tissue remodeling and cell-cell communication were upregulated in FSP1-FBs. Several studies, including from our group, have suggested that Secreted Frizzled-related protein 2 (sFRP2), a putative wnt pathway inhibitor, mediates wound repair by inhibiting fibrosis. We developed a novel mouse model in which we can induce expression of sFRP2 in activated FBs following injury. We found that early post-injury sFRP2 activation resulted in reduced fibrosis after myocardial, kidney and skin injuries without inhibiting tissue repair. Interestingly, our preliminary data showed that sFRP2 inhibited Col I synthesis and TGF? signaling (but not Wnt signaling) only in ?SMA-FBs but not in FSP-1 FBs in vitro. As such, sFRP2 represents an anti-fibrotic paracrine factor which may reduce tissue fibrosis by exerting distinct molecular effects on the post-injury (i.e. activated) FB subtypes. At the conclusion of this research proposal we will have characterized the cellular and functional heterogeneity of the major injury-activated FB populations and also have elucidated the mechanistic basis of the pro-reparative, antifibrotic effects of sFRP2 via its targeted and distinct effects on ?-SMA-expressing FBs.

IC Name
NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
  • Activity
    R01
  • Administering IC
    GM
  • Application Type
    7
  • Direct Cost Amount
    110000
  • Indirect Cost Amount
    46200
  • Total Cost
    156200
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    859
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIGMS:156200\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    SAT
  • Study Section Name
    Surgery, Anesthesiology and Trauma Study Section
  • Organization Name
    TENNESSEE STATE UNIVERSITY
  • Organization Department
    BIOLOGY
  • Organization DUNS
    108814179
  • Organization City
    NASHVILLE
  • Organization State
    TN
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    372091561
  • Organization District
    UNITED STATES