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

批准号：
10912839
负责人：
Martha U Gillette
金额：
$ 48.03万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10912839
关键词：
Address Aging Animal Model Astrocytes Award Behavior Biomimetics Blood Blood - brain barrier anatomy Blood Coagulation Factor Blood Vessels Blood coagulation Brain Brain Diseases Circadian Rhythms Coagulation Process Cognition Disorders Consultations Crying Dementia Deterioration Development Disease Disease Management Endothelial Cells Endothelium Engineering Event Exhibits Extravasation Fibrin Fibrinogen Gait Genes Goals Grant Health Promotion Hemorrhage Human Hypertension Incidence Infection Inflammation Ischemic Stroke Knowledge Lead Liquid substance Microfluidics Microglia Modeling Mus Names Nerve Degeneration Neurons Optics Outcome Pattern Personal Satisfaction Persons Pharmacotherapy Phase Physiology Plasma Plasminogen Activator Plasminogen Activator Inhibitor 1 Predisposition Reporter Reporter Genes Reporting Research Role Side Sleep Sleep Deprivation Stress Stroke Stroke prevention Syndrome System Testing Therapeutic Thrombin Tight Junctions Time Transgenes Traumatic Brain Injury United States Vascular Endothelial Cell Vascular Endothelium Venus Wakefulness brain parenchyma brain tissue cell injury cerebral microbleeds cerebrovascular circadian circadian pacemaker circadian regulation design disorder prevention glial activation high reward high risk in vivo induced pluripotent stem cell inhibitor innovation insight member millimeter mimicry neuron loss neurovascular novel pressure public health relevance response stem cells stroke incidence tool translational applications translational model vascular factor

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.

脑微粒（CMB）和微毛发（CMHS）是由于血液渗漏而引起的脑界面（BBI）。退化。受伤和中风的后遗症，尤其是在美国造成795,000次。 CMBS和出血/缺血性中风的发生不是随机的，而是在早日或晚上的聚类。了解BBI的昼夜节律有关血液的脆弱性在体内或通过片上模型很难研究，并且没有trug乱的tr毛tr痕治疗。该提案响应FOA RFA-HL-20-021。研究血液障碍和相关界面的血液成分，以促进您开发更多更强迫的神经血管血管模型，用于具有直接相关性的转化应用应用对于人类，这是R61 /R33探索性 /发展性分阶段奖。血液泄漏脆弱性的动态有限，我们旨在创建新的仿生脑运输模仿凝结系统和昼夜节律的模型。检查凝血因子和昼夜节律的相互作用的平台1）血液/血管组件和2）动态血管在我们建议的昼夜节律上遍布BBI 通过培养含有时钟 - 基因记者的人类眼细胞来培养BBI的昼夜节律动力学在“大脑”室中具有偏振层胶质细胞，神经元和小胶质细胞的侧面。组装促进增强平台创建所需的专业知识，并密切建模 BBI的贡献将是：Han - Microfluidics和Biotransport分析； BBI的工程；和通量，并咨询有关血液凝血因子和循环记者的obrietan的咨询。 Transgene。在3-5年（R33）中，利用这些工具来实现我们的研究目标。 BBI在人脑中的bbi，并在振荡性的昼夜节奏thacle thacle t的背景下进行探究。生理学和行为，包括睡眠和清醒。交叉点，我们将获得对新兴视图的见解睡眠，感染的压力和衰老。大脑和神经血管功能的血液凝结将有助于发展针对不良小脑事件的临时性事件的治疗机会，包括高血压，认知障碍和痴呆症以及步态综合征。