PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome

Information

  • Research Project
  • 10171430
  • ApplicationId
    10171430
  • Core Project Number
    P01HL131474
  • Full Project Number
    2P01HL131474-06
  • Serial Number
    131474
  • FOA Number
    PAR-18-405
  • Sub Project Id
    9967
  • Project Start Date
    7/15/2016 - 7 years ago
  • Project End Date
    5/31/2026 - a year from now
  • Program Officer Name
    SARKAR, RITA
  • Budget Start Date
    5/1/2021 - 3 years ago
  • Budget End Date
    4/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    06
  • Suffix
  • Award Notice Date
    8/26/2021 - 2 years ago

PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome

Project Summary, UC San Diego, Project 3 The aims of Project 3 address the central hypothesis of the overall program: Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Project 3 will investigate remodeling of the vascular glycocalyx induced by sepsis and how these changes affect host response and survival in mice. The proposed research engages all of the core facilities of the program and draws on the combined expertise of the Project Leaders and Core Leaders in infection and sepsis, inflammatory biology, coagulation, proteomics and glycobiology. From recent literature and preliminary data, it is well known that sepsis induces changes in the composition of plasma glycoproteins and shedding of the vascular endothelial glycocalyx, leading to vascular dysfunction and high mortality. However, little information is available about the composition of the vascular proteome and glycoproteome and how it changes in response to different infectious agents. Over the last grant cycle, we developed an in vivo tagging method that allows assessment of the vascular proteome in different organs. We showed that infection by methicillin-resistant Staphylococcus aureus (MR) results in remodeling of the vascular proteome in an organ-specific manner, leading to the discovery of proteoglycan 4 and factors that modulate hyaluronan metabolism as potential novel markers of infection. We also showed that heparan sulfate produced by the vascular endothelium plays an important role in determining the severity and outcome of sepsis in mice. In the liver, undersulfation of endothelial heparan sulfate protects against the inflammatory response and coagulopathy induced by MR. However, in the heart, pathological changes take place that correlate with hypersensitivity to Staphylococcus aureus alpha-hemolysin, a key virulence factor. In the next cycle, we will expand the in vivo tagging method to include other common bacterial pathogens that cause sepsis in humans in order to identify operative pathogenic mechanisms and to determine if sepsis can be stratified by responses in the vascular wall to different pathogens. We will examine the mechanism by which heparan sulfate modulates alpha-hemolysin sensitivity. We will determine if the induction of proteoglycan 4 and hyaluronan metabolism are general hallmarks of sepsis and if these factors serve a protective role. We also showed that proteoglycan 4 and hyaluronan accumulate in human plasma samples from patients with sepsis. We will correlate these markers with clinical information about the patients to determine if these markers stratify sepsis and whether they have value as diagnostic or prognostic markers. The overarching goal is to understand if infection-induced remodeling of the vascular glycoproteome provides a window to identify disease mechanisms and a way to stratify sepsis across time, different infectious agents, and during disease resolution.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    P01
  • Administering IC
    HL
  • Application Type
    2
  • Direct Cost Amount
    354358
  • Indirect Cost Amount
    119045
  • Total Cost
  • Sub Project Total Cost
    473403
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NHLBI:473403\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    HLBP
  • Study Section Name
    Heart, Lung, and Blood Initial Review Group
  • Organization Name
    SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES