Coupling regional brain tissues with tissue chips

将区域脑组织与组织芯片耦合

• 批准号: 10527012
• 负责人: Larry J. Millet
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527012
• 关键词: ANXA5 gene; Agonist; Alcoholism; Anatomy; Animal Model; Animals; Award; Axon; Base of the Brain; Behavior; Biological Assay; Biological Process; Brain; Brain region; Cardiovascular system; Cell Nucleus; Cells; Cerebrospinal Fluid; Clinical Trials; Coculture Techniques; Complex; Coupling; Cues; Dense Core Vesicle; Diabetes Mellitus; Drug Targeting; Event; Fluorescence Microscopy; Goals; Health; Hippocampus (Brain); Human; Hypothalamic structure; Image; Immune; In Vitro; Individual; Instruction; Intervention; Knowledge; Location; Measures; Mental Depression; Mental disorders; Metabolic; Metabolic Diseases; Microfluidics; Microglia; Microscopy; Midbrain structure; Modeling; Molecular; Molecular Conformation; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences Research; Neurosecretory Systems; Neurosphere; Nucleus Accumbens; Organ Model; Outcome; Oxytocin; PHluorin; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Propidium Diiodide; Psychiatric therapeutic procedure; Rattus; Recombinant adeno-associated virus (rAAV); Regulation; Resolution; Signal Transduction; Slice; Small Business Technology Transfer Research; Source; Surface; Synapses; System; Testing; Thalamic structure; Therapeutic; Tissue Microarray; Tissue imaging; Tissues; Transgenic Organisms; Vasopressins; Ventral Striatum; Vesicle; Viral; Work; autism spectrum disorder; axon growth; brain tissue; circadian; circadian pacemaker; communication behavior; drug candidate; drug testing; fluorophore; high resolution imaging; imaging study; immunoregulation; improved; in vivo; in vivo imaging; interstitial; magnocellular; melanocortin receptor; migration; miniaturize; nanoscale; nervous system disorder; neurogenesis; organ on a chip; post-traumatic stress; pre-clinical; preclinical study; social; social cognition; therapeutic target; tissue culture; tissue preparation; tool; translational neuroscience; vesicular release

Project Summary The hypothalamus is the master regulator of the neuroendocrine system, it synapses to multiple brain regions and coordinates physiological functions of the body. Magnocellular neurons (MCN) are key producers of oxytocin and vasopressin, they regulate neuroendocrine functions and differentially secrete oxytocin into the brain, the cerebrospinal fluid, and the circulatory system. How MCN differentially regulate oxytocin release remains unresolved. Oxytocin is involved in and studied as a candidate treatment for psychiatric and metabolic conditions such as autism, depression, and post-traumatic stress. Miniaturized models of organs and tissues are indispensable tools for bridging the gap between preclinical animal models and clinical trials. Human and animal microfluidic tissue-chips provide unparalleled control and access to cells and tissues where anatomical and technical barriers preclude in vivo studies. We will create a microfluidic-based brain tissue chip for coupling brain slices and primary neurospheres from at least two regions of the brain. Surface-patterned guidance cues will be used to direct the growth of axons from oxytocinergic magnocellular neurons toward target brain tissues. Our microfluidic system will allow for brain-to-synapse connections for the direct observation of nano-scale oxytocin vesicles to achieve detailed studies of how different drugs influence the locations and dynamics of oxytocin vesicle release. More generally, potential applications of our brain-to-brain tissue culture system could include the ability to connect multiple brain regions in vitro for the benefit of immune regulation studies, neuroendocrine regulation studies, neurogenesis and migration studies, and how drugs influence molecular and cellular dynamics.

项目摘要 下丘脑是神经内分泌系统的主要调节器，它与多个大脑突触 区域和协调身体的生理功能。大细胞神经元(MCN)是关键 催产素和加压素的产生者，它们调节神经内分泌功能并差异化地分泌 催产素进入大脑、脑脊液和循环系统。MCN如何与众不同 调节催产素的释放仍未解决。催产素参与并被研究为候选治疗方法 适用于精神和代谢疾病，如自闭症、抑郁症和创伤后应激障碍。 器官和组织的微型模型是弥合两者之间差距的不可或缺的工具 临床前动物模型和临床试验。人类和动物微流控组织芯片提供 无与伦比的对细胞和组织的控制和访问，在体内的解剖和技术障碍是不可能的 学习。我们将创建一种基于微流控技术的脑组织芯片，用于连接脑片和原代细胞 来自大脑至少两个区域的神经球。将使用表面图案的指导线索来指导 从催产素能大细胞神经元向靶脑组织生长的轴突。我们的微流体 该系统将允许脑到突触的连接，以直接观察纳米尺度的催产素 囊泡实现不同药物如何影响催产素的位置和动态的详细研究 囊泡释放。更广泛地说，我们的脑对脑组织培养系统的潜在应用可能 包括在体外连接多个大脑区域的能力，以利于免疫调节研究， 神经内分泌调节研究、神经发生和迁移研究，以及药物如何影响分子 和细胞动力学。