CAREER: Mitochondrial Transcellular Communication in the Nervous System: Mechanisms of Action and Student Training Opportunities

职业：神经系统中的线粒体跨细胞通讯：作用机制和学生培训机会

• 批准号: 2235079
• 负责人: Martha Bhattacharya
• 金额: $ 110万
• 依托单位: University of Arizona
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2235079&HistoricalAwards=false
• 关键词: CAREER; Mitochondrial; Transcellular; Communication; Nervous

Most neurons in your brain are irreplaceable and must function in their circuits for life. To maintain the brain health, stressed or damaged neurons must receive support from surrounding cells to increase their chances of survival. To communicate with each other, both neurons and non-neuronal cells called glia release molecules that communicate their health status and elicit appropriate responses. Remarkably, one of the communication strategies that glia and neurons use involves the transfer of entire cellular organelles called mitochondria whose primary job is to produce energy. While the transfer of healthy, intact mitochondria improves neuronal function, the transfer of faulty mitochondria is toxic. How glia and neurons coordinate requests for and deliveries of mitochondria to ensure brain health is an unanswered question but one of vital importance. This project will elucidate the triggers for mitochondrial transfer, the cellular machinery used in their release, and the uptake mechanisms that integrate mitochondria into recipient cells. In doing so, the research will provide a window into a key process that could in the future be exploited to improve brain function throughout life. To perform aspects of this project, undergraduate students will participate in a unique credit-bearing, team-based research experience focused on neuron-glia communication and using the fruit fly as a model system. Undergraduate students will also participate in an outreach event to local elementary and middle school students. Taken together, the project will reveal new modes of cellular communication that underlie brain health and will provide training opportunities for the future scientific workforce.This project will establish the mechanisms and regulation of mitochondrial trans-cellular transfer (mitoTCT) in vivo by deploying an innovative combinatorial strategy of genetics, 3D microscopy, and imaging flow cytometry (iFACS) in the Drosophila nervous system. Using dual binary expression systems, neuronal and glial membranes and mitochondria will be labeled with four colors, facilitating unambiguous identification of the sources and directions of mitoTCT. In Aim 1, the project will elucidate key regulators of mitoTCT rate in vivo. This aim will test the hypothesis that nerve injury and/or excess neuronal activity can trigger mitoTCT from glia to neurons. In Aim 2, the project will determine the mechanism(s) by which mitochondria are transferred between glia and neurons. Three proposed modes of transfer (tunneling nanotubes, extracellular vesicles, and release of free mitochondria) will be evaluated by inhibition of each mechanism in a cell type specific manner. In both aims, the health status of mitochondria will be evaluated using genetically encoded redox sensors, which will determine whether the mode of action is leading to rescue or toxicity of recipient cells. This research will advance fundamental knowledge of neuron-glia communication via mitochondria and will illuminate how we might harness mitochondrial transfer for the benefit of neuronal health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

大脑中的大多数神经元都是不可替代的，并且必须终生在其回路中发挥作用。为了维持大脑健康，受到压力或受损的神经元必须得到周围细胞的支持，以增加其生存机会。为了相互沟通，神经元和称为神经胶质细胞的非神经元细胞都会释放分子来传达其健康状态并引起适当的反应。值得注意的是，神经胶质细胞和神经元使用的通讯策略之一涉及称为线粒体的整个细胞器的转移，线粒体的主要作用是产生能量。虽然健康、完整的线粒体的转移可以改善神经元功能，但有缺陷的线粒体的转移是有毒的。神经胶质细胞和神经元如何协调线粒体的需求和传递以确保大脑健康是一个尚未解答的问题，但却是至关重要的问题之一。该项目将阐明线粒体转移的触发因素、释放线粒体时使用的细胞机制，以及将线粒体整合到受体细胞中的摄取机制。在此过程中，这项研究将为了解一个关键过程提供一个窗口，该过程将来可用于改善一生中的大脑功能。为了完成该项目的各个方面，本科生将参与一项独特的、以学分为基础的、基于团队的研究体验，重点关注神经元-神经胶质细胞的通讯，并使用果蝇作为模型系统。本科生还将参加针对当地中小学生的推广活动。总而言之，该项目将揭示大脑健康的新细胞通讯模式，并为未来的科学工作者提供培训机会。该项目将通过在果蝇神经系统中部署遗传学、3D显微镜和成像流式细胞术（iFACS）的创新组合策略，建立体内线粒体跨细胞转移（mitoTCT）的机制和调节。使用双二元表达系统，神经元和神经胶质膜以及线粒体将用四种颜色标记，有助于明确识别 mitoTCT 的来源和方向。在目标 1 中，该项目将阐明体内 mitoTCT 速率的关键调节因子。这一目标将检验神经损伤和/或过度的神经元活动可以触发从神经胶质细胞到神经元的 mitoTCT 的假设。在目标 2 中，该项目将确定线粒体在神经胶质细胞和神经元之间转移的机制。将通过以细胞类型特异性方式抑制每种机制来评估三种拟议的转移模式（隧道纳米管、细胞外囊泡和游离线粒体的释放）。在这两个目标中，将使用基因编码的氧化还原传感器评估线粒体的健康状况，这将确定作用模式是否会导致受体细胞的拯救或毒性。这项研究将推进通过线粒体进行神经元-神经胶质细胞通讯的基础知识，并将阐明我们如何利用线粒体转移来造福神经元健康。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。