Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury

Information

  • Research Project
  • 10271701
  • ApplicationId
    10271701
  • Core Project Number
    P20GM113125
  • Full Project Number
    2P20GM113125-06
  • Serial Number
    113125
  • FOA Number
    PAR-19-312
  • Sub Project Id
    6562
  • Project Start Date
    5/15/2016 - 8 years ago
  • Project End Date
    5/31/2026 - a year from now
  • Program Officer Name
  • Budget Start Date
    7/1/2021 - 3 years ago
  • Budget End Date
    6/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    06
  • Suffix
  • Award Notice Date
    8/25/2021 - 3 years ago
Organizations

Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury

PROJECT SUMMARY Dementia is a debilitating syndrome with many incapacitating symptoms requiring dependent care that is emotionally and financially burdensome for patients and their families. Dementia is the 6th leading cause of death in the United States with 47.5 million people worldwide currently living with dementia which is projected to reach 75.6 million by 2030 and 135.5 million by 2050. Unfortunately, no therapies to treat dementia exist, indicating a critical and urgent need for a better understanding of how dementia is initiated and progresses so that new therapeutic approaches can be developed. Age-related stiffening of the large elastic arteries is a major contributor to dementia but the mechanism(s) by which this occurs remain unknown. In healthy individuals, pulsatile flow in large vessels is converted to continuous flow in cerebral µvasculature via pulsatility dampening by large arteries. Repeated cycles of distension and relaxation over time induce irreversible elastin fragmentation in large arteries which is replaced by stiffer collagen thereby diminishing compliance and dampening. This results in the conversion from continuous to pulsatile flow in cerebral microvasculature accompanied by increases in pulse pressure and pulse wave velocity. These pathological hemodynamics have been linked to cognitive decline via neuronal injury, synaptic dysfunction, and neurodegeneration. While most hypotheses focus on shear- induced injury mechanisms, endothelial cells and neurons are also sensitive to strain. We hypothesize that induction of cyclic strain, in the microvessel wall and adjacent tissue, due to the conversion to pulsatile flow, exacerbates shear-induced brain microvascular endothelial cell (BMEC) dysfunction and is the primary cause of neuronal injury. We will test our hypotheses via fulfillment of two aims. (1) Investigate the independent, and combined influences of, conversion to, and increases in, cyclic shear stress and cyclic strain on BMEC dysfunction and inflammation. We hypothesize that conversion from continuous to pulsatile flow, and an increase in pulse wave velocity, induce BMEC dysfunction and inflammation via exposure to increased cyclic shear stress. We further hypothesize that cyclic strain in the microvascular wall, and increase in strain magnitude due to increased pulse pressure, exacerbate shear-induced BMEC dysfunction. (2) Investigate the influence of cyclic strain on neuronal injury. We hypothesize that as pulse pressure increases, the associated increase in strain will induce neuronal injury via strain propagation into tissue and neurons adjacent to the vessel and that this process worsens with age-related brain softening. The results of this proposal will provide significant insight into how pathological hemodynamics induced by arterial stiffening lead to BMEC and neuronal injury.

IC Name
NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
  • Activity
    P20
  • Administering IC
    GM
  • Application Type
    2
  • Direct Cost Amount
    211308
  • Indirect Cost Amount
    109207
  • Total Cost
  • Sub Project Total Cost
    320515
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NIGMS:320515\
  • Funding Mechanism
    RESEARCH CENTERS
  • Study Section
    ZGM1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    UNIVERSITY OF DELAWARE
  • Organization Department
  • Organization DUNS
    059007500
  • Organization City
    NEWARK
  • Organization State
    DE
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    197160099
  • Organization District
    UNITED STATES