Modulation of the TLR4-Lyn interaction in SAH

Information

  • Research Project
  • 10274359
  • ApplicationId
    10274359
  • Core Project Number
    R01NS109174
  • Full Project Number
    7R01NS109174-03
  • Serial Number
    109174
  • FOA Number
    PA-18-590
  • Sub Project Id
  • Project Start Date
    10/2/2020 - 4 years ago
  • Project End Date
    11/30/2023 - a year ago
  • Program Officer Name
    KOENIG, JAMES I
  • Budget Start Date
    12/1/2020 - 4 years ago
  • Budget End Date
    11/30/2021 - 3 years ago
  • Fiscal Year
    2021
  • Support Year
    03
  • Suffix
  • Award Notice Date
    2/9/2021 - 3 years ago

Modulation of the TLR4-Lyn interaction in SAH

Hemorrhagic stroke affects 160,000 Americans per year and over half of these patients will die by the end of the year. Treatment for both forms of hemorrhagic stroke, intraparenchymal hemorrhage and aneurysmal subarachnoid hemorrhage, have been at a virtual standstill for the last 40 years, and not due to lack of effort. Perhaps the reason for the lack of progress is an inability to effectively address the cerebral inflammation secondary to the extravasated red blood cell (RBC) burden. In animal models of hemorrhagic stroke, microglia (MG), the tissue resident macrophages of the brain, have been shown to play a critical role in RBC-induced cerebral inflammation. The MG receptor that is responsible for initiating RBC-induced cerebral inflammation is Toll Like Receptor 4 (TLR4). In mouse models of hemorrhagic stroke, MG TLR4 responds to the breakdown products of RBCs to initiate cerebral inflammation. While inhibiting MG TLR4 would seem feasible to prevent cerebral inflammation in hemorrhagic stroke, this strategy carries a significant risk of immunosuppression. Modulation of non-canonical TLR4 pathways that are downstream of TLR4 may offer some respite against MG-mediated cerebral inflammation. Lyn kinase (Lyn) is a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells. Lyn is unique in the SFK family in that it has both stimulatory and feedback-inhibitory pathways in B cell receptor signaling that can lead to ligand tolerance. Evidence for Lyn kinase regulation of TLR4 signaling in response to bacterial PAMPs is scant, contradictory, and cell type dependent. Understanding Lyn regulation of TLR4 signaling in response to an RBC stimulus in MG is novel, and could allow for the modulation of cerebral inflammation in hemorrhagic stroke. Our lab has found that MG TLR4-Lyn signaling is important for RBC-induced inflammation and RBC phagocytosis. Our preliminary data indicates that modulation of this pathway does indeed decrease neuronal apoptosis, in vitro. We hypothesize that modulation of this pathway in MG can improve outcome after SAH and possibly other forms of hemorrhagic stroke.

IC Name
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
  • Activity
    R01
  • Administering IC
    NS
  • Application Type
    7
  • Direct Cost Amount
    296918
  • Indirect Cost Amount
    146974
  • Total Cost
    443892
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    853
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NINDS:443892\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMBG
  • Study Section Name
    Cellular and Molecular Biology of Glia Study Section
  • Organization Name
    FLORIDA ATLANTIC UNIVERSITY
  • Organization Department
    NONE
  • Organization DUNS
    004147534
  • Organization City
    BOCA RATON
  • Organization State
    FL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    334316424
  • Organization District
    UNITED STATES