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Bioengineer a humanized Autonomic Neurovascular Innervation on a Chip

在芯片上设计人性化的自主神经血管神经支配

基本信息

批准号：
10195691
负责人：
Guohao Dai
金额：
$ 43.18万
依托单位：
NORTHEASTERN UNIVERSITY
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：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195691
关键词：
Addison&apos s disease Address Adrenal Glands Animal Model Arteries Arteriovenous fistula Autonomic nervous system Autonomic nervous system disorders Biomedical Engineering Blood Circulation Blood Vessels Blood flow Breathing Bypass Cardiovascular Diseases Cell Communication Cell Differentiation process Cell Proliferation Cells Chick Embryo Chronic Clinical Coculture Techniques Controlled Study Coronary Coronary Artery Bypass Cues Cushing Syndrome Development Digestion Embryonic Development Endothelial Cells Endothelium Environment Event Fatigue Functional disorder Future Goals Harvest Hemodialysis Hyperplasia Hypertension Impairment Knowledge Lead Link Methods Modeling Molecular Monitor Morbidity - disease rate Nerve Neurons Neurotransmitters Operative Surgical Procedures Organ Organ Transplantation Outcome Parasympathetic Nervous System Patients Peripheral arterial disease Phenotype Pheochromocytoma Physiologic pulse Physiological Regulation Research Reverse Transcriptase Polymerase Chain Reaction Saphenous Vein Signal Transduction Smooth Muscle Myocytes Stains System Testing Therapeutic Intervention Time Tissue Engineering Tissue Microarray Vascular Endothelial Cell Vascular Graft Vein graft Veins Venous autonomic nerve controlled release design experimental study functional outcomes graft failure hemodynamics improved internal thoracic artery mortality nerve supply neural stimulation neuromechanism neurotransmission neurotransmitter release neurovascular novel novel strategies optogenetics public health relevance relating to nervous system response tool

项目摘要

SUMMARY A significant amount of vein grafts fail after 5 years, which leads to the morbidity and mortality of patients receiving vein graft procedures. Successful adaptation of vein grafts to arterial hemodynamics is the key to a satisfactory clinical outcome. Nevertheless, vein grafts do not become an artery under arterial circulation. The incomplete adaptation of vein grafts to arterial hemodynamics may be the primary reason of vein graft failure. One of the missing links in the vein graft is the lack of innervation, whereas arteries are closely associated with the sympathetic/parasympathetic nerves. A recent study in embryonic development suggested that sympathetic innervation is critical for the proper development of arteries through releasing sympathetic neurotransmitters, raising an exciting possibility that providing innervation to the vein graft may facilitate the better switch of vein to artery, thus potentially leading to better clinical outcomes. To explore this possibility, here we propose to examine autonomic neural derived signals on the arterialization of vascular endothelial cells (ECs) and their impact on smooth muscle cells (SMC) phenotypes, by establishing a novel humanized vascular innervation model on a microphysiological chip. In this model, sympathetic/parasympathetic neurons, vascular endothelial cells and smooth muscle cells will be co-cultured and neural activity will be precisely controlled via optogenetic tools. We will study the impact of sympathetic/parasympathetic stimulation on the arterial differentiation of ECs and phenotypic modulation of SMCs. This research will generate fundamental knowledge on autonomic nerve signals on vascular cell fate, thereby having a direct impact on developing new methods to improve arterialization of vascular grafts.

摘要大量的静脉移植在5年后失效，这导致了患者的发病率和死亡率。接受静脉移植手术。移植静脉与动脉血流动力学的成功适应是临床效果满意。然而，静脉移植物在动脉循环下不能成为动脉。这个移植静脉对动脉血流动力学的不完全适应可能是移植静脉失败的主要原因。静脉移植中缺失的环节之一是缺乏神经支配，而动脉与交感神经/副交感神经。最近一项关于胚胎发育的研究表明，交感神经支配通过释放交感神经对动脉的正常发育至关重要神经递质，增加了一种令人兴奋的可能性，即为静脉移植物提供神经可能有助于更好地将静脉转换为动脉，从而潜在地导致更好的临床结果。为了探索这种可能性，在这里，我们建议检查自主神经派生的信号关于血管内皮细胞的动脉化。通过建立一种新的人源化细胞及其对平滑肌细胞(SMC)表型的影响微生理芯片上的血管神经模型。在这个模型中，交感/副交感神经元，血管内皮细胞和平滑肌细胞将进行共培养，神经活动将精确通过光遗传工具控制。我们将研究交感神经/副交感神经刺激对血管内皮细胞的动脉分化和SMC的表型调节。这项研究将产生基本的了解自主神经信号对血管细胞命运的影响，从而对开发新的方法改善血管移植物的动脉化。