Dynamic Circadian Regulation of the Blood-Brain Interface in a Human Brain-mimicking Microfluid Chip

模拟人脑微流体芯片中血脑界面的动态昼夜节律调节

基本信息

项目摘要

Cerebral microbleeds (CMBs) and microhemorrhages (CMHs) result from blood leakage across the blood- brain interface (BBI). Subsequent millimeter-sized blood clots lead to inflammation, cellular injury, and neuro- degeneration. Such CMBs are associated with deterioration of BBI integrity with aging, disease, traumatic brain injury, and the sequelae of strokes, which impact >795,000 people in the United States every year. Notably, CMBs and hemorrhagic/ischemic stroke occurrence is not random, but rather clusters in early day or evening. Understanding of the circadian dynamics of the BBI with respect to vulnerability to blood leakage is limited. It has been difficult to study in vivo or via on-chip models and there is no drug treatment. In addressing this gap, this proposal responds to FOA RFA-HL-20-021. The purpose of this FOA is to support high risk/high reward research on the blood component of the Blood-Brain Barrier and the associated Interface to facilitate the development of a more complete neurovascular-blood model for translational applications with direct relevance to humans. It is an R61/R33 Exploratory /Developmental Phased Award. Because knowledge of the circadian dynamics in BBI vulnerability to blood leakage is limited, we aim to create a new biomimetic brain transport model with mimicry of the coagulation system and circadian rhythm. We will develop an innovative microfluidic platform to examine interactions of coagulation factors and circadian oscillations of both 1) the blood/vascular components and 2) dynamic vascular pressure across the BBI over the circadian cycle. We propose to reproduce circadian dynamics of the BBI by culturing human endothelial cells containing a clock-gene reporter on the ‘vascular’ side with polarized astrocytes, neurons, and microglia in the ‘brain’ compartment. This project assembles the expertise needed to facilitate the creation of enhanced platforms that more closely model the human BBI. Contributions of team members will be: Han–Microfluidics and biotransport analysis; Kong– engineering of BBI; Gillette–Assemble/validate a human iPSC circadian reporter-in-chip and assess rhythms and fluxes, and consultation from Flick on blood coagulation factors and Obrietan on the circadian reporter transgene. This grant will be separated into 2 phases: Focus in YR 1-2 (R61) will be on establishing tools and in YR 3-5 (R33) on utilizing those tools to achieve our research goals. This will enable us to replicate dynamics of the BBI in human brain and to probe it in the context of the oscillatory circadian cycle that drives integrative physiology and behavior, including sleep and wakefulness. By targeting both sides of the BBI and their intersection, we will gain insights into the emerging view that the BBI is plastic, changing with time-of-day, loss of sleep, the stress of infection, and aging. This has significant implications for the role of the circadian clock in blood coagulation in the brain and neurovascular function. The outcome will contribute to developing therapeutic opportunities that target the temporal occurrence of adverse cerebrovascular events, including hypertension, cognitive disorders and dementias, and gait syndromes.
脑微出血(CMBs)和微出血(CMHs)是由血液渗漏引起的

项目成果

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Martha U Gillette其他文献

Martha U Gillette的其他文献

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{{ truncateString('Martha U Gillette', 18)}}的其他基金

Dynamic Circadian Regulation of the Blood-Brain Interface in a Human Brain-mimicking Microfluid Chip
模拟人脑微流体芯片中血脑界面的动态昼夜节律调节
  • 批准号:
    10912839
  • 财政年份:
    2021
  • 资助金额:
    $ 85.27万
  • 项目类别:
High Resolution Analysis of miR125b in Dendrites via Microfluidic Devices
通过微流体装置对树突中的 miR125b 进行高分辨率分析
  • 批准号:
    8571230
  • 财政年份:
    2013
  • 资助金额:
    $ 85.27万
  • 项目类别:
Nano-Scale Processes of Dendrogenesis
树突发生的纳米级过程
  • 批准号:
    7882602
  • 财政年份:
    2009
  • 资助金额:
    $ 85.27万
  • 项目类别:
Nano-Scale Processes of Dendrogenesis
树突发生的纳米级过程
  • 批准号:
    7740046
  • 财政年份:
    2009
  • 资助金额:
    $ 85.27万
  • 项目类别:
Neuropeptidomics of Clock-to-Clock Coupling
时钟与时钟耦合的神经肽组学
  • 批准号:
    7736240
  • 财政年份:
    2009
  • 资助金额:
    $ 85.27万
  • 项目类别:
Neuropeptidomics of Clock-to-Clock Coupling
时钟与时钟耦合的神经肽组学
  • 批准号:
    7924746
  • 财政年份:
    2009
  • 资助金额:
    $ 85.27万
  • 项目类别:
Actin-based Neuronal State Changes
基于肌动蛋白的神经元状态变化
  • 批准号:
    7321299
  • 财政年份:
    2007
  • 资助金额:
    $ 85.27万
  • 项目类别:
Actin-based Neuronal State Changes
基于肌动蛋白的神经元状态变化
  • 批准号:
    7488953
  • 财政年份:
    2007
  • 资助金额:
    $ 85.27万
  • 项目类别:
Actin-based Neuronal State Changes
基于肌动蛋白的神经元状态变化
  • 批准号:
    7683239
  • 财政年份:
    2007
  • 资助金额:
    $ 85.27万
  • 项目类别:
Actin-based Neuronal State Changes
基于肌动蛋白的神经元状态变化
  • 批准号:
    7898831
  • 财政年份:
    2007
  • 资助金额:
    $ 85.27万
  • 项目类别:

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