The mechanical control of neuronal maturation

神经元成熟的机械控制

• 批准号: BB/N006402/1
• 负责人: Kristian Franze
• 金额: $ 66.5万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN006402%2F1
• 关键词: mechanical; control; neuronal; maturation

During the development of the nervous system, billions of neurons have to extend long processes (dendrites and axons), which grow over large distances, become electrically active, connect to the right partners and communicate with them. Through these connections neurons form highly organised networks and transmit information in form of electrical and chemical signals that govern our functions. Each of these developmental steps is critical, and any failure may have devastating consequences for the whole organism.Almost everything we know about these processes is related to the communication between neurons and their environment via molecules and electrical signals, which is what biology has focused on during the past decades. However, neurons live in a physical world and obey physical laws. When neurons grow through tissue, they not only chemically but also mechanically interact with their environment. As bicycling is easier for us along a paved road than along a sandy beach, the mechanical properties of the tissue through which neurons grow will also strongly influence, for example, how fast they can grow and develop.Importantly, the local stiffness of brain tissue varies depending on the region in the brain, and it changes during development, ageing, neurological diseases and after injuries. While brain tissue is usually extremely soft, it becomes stiffer during ageing (in men more than in women), and under pathological conditions it can change dramatically in structure and stiffness. Prominent examples are scarring after injury or stroke, and the formation of rigid plaques or tangles in diseases such as Alzheimer's. These changes in local tissue stiffness may strongly influence neuronal function. Neuronal function, which develops as neurons mature, is characterised by their capability to generate and transmit electrical signals. However, how the mechanical environment regulates the maturation of the electrical activity of neurons and their connections to other neurons (synapses) is not known.To address this important gap in our knowledge, which has important implications not only for the development of the nervous system but also for different neurological disorders, we have put together a multidisciplinary team with years of experience in neuroscience and biophysics. The proposed project involves cutting edge neurobiology, mechanobiology, electrophysiology, molecular biology, biophysics and engineering approaches, whose combination will advance the field and provide powerful tools beyond the state of the art.We will first determine which mechanical properties the environment must have to optimally promote neuronal maturation and activity, by comparing how neurons develop in mechanically different custom-built environments. We will then use a tiny leaf spring ('cantilever') to push and pull on neurons with well-controlled forces, which are as small as the forces cells usually exert on their environment, and simultaneously measure the electrical currents that flow through these neurons. These experiments will reveal how mechanical signals alter neuronal activity and maturation. Finally, we want to understand how neurons perceive and translate these mechanical stimuli. To do this, we will identify force sensors in the neurons, and investigate how their specific activation changes cellular function.The knowledge gained in this project will not only illuminate a new facet of the development of the nervous system. Mechanical signalling might also be the missing link to understanding different developmental disorders and neurological diseases. Our research, bridging the gap between the life and physical sciences, may thus ultimately lead to important changes in how we treat patients suffering of neurological disorders.

在神经系统的发育过程中，数十亿的神经元必须延伸长过程（树突和轴突），这些过程在很远的距离上生长，变得电活跃，连接到正确的伙伴并与他们交流。通过这些连接，神经元形成高度组织化的网络，并以电信号和化学信号的形式传递信息，控制我们的功能。这些发育步骤中的每一步都是至关重要的，任何失败都可能对整个生物体造成毁灭性的后果。我们所知道的几乎所有这些过程都与神经元和它们的环境之间通过分子和电信号的交流有关，这是生物学在过去几十年里所关注的。然而，神经元生活在物理世界中，遵守物理定律。当神经元在组织中生长时，它们不仅在化学上而且在机械上与环境相互作用。就像我们在铺有路面的道路上骑车比在沙滩上骑车更容易一样，神经元赖以生长的组织的机械特性也会强烈地影响它们生长和发育的速度。重要的是，脑组织的局部硬度取决于大脑的区域，它在发育、衰老、神经系统疾病和受伤后都会发生变化。虽然大脑组织通常是非常柔软的，但随着年龄的增长，它会变得更硬（男性比女性更硬），在病理条件下，它的结构和硬度会发生巨大变化。突出的例子是受伤或中风后留下的疤痕，以及在阿尔茨海默氏症等疾病中形成的刚性斑块或缠结。这些局部组织硬度的变化可能强烈影响神经元功能。神经元功能随着神经元的成熟而发展，其特点是它们具有产生和传输电信号的能力。然而，机械环境如何调节神经元电活动的成熟及其与其他神经元（突触）的连接尚不清楚。为了解决这一重要的知识缺口，这不仅对神经系统的发展，而且对不同的神经系统疾病都有重要的影响，我们组建了一个具有多年神经科学和生物物理学经验的多学科团队。该项目涉及最前沿的神经生物学、机械生物学、电生理学、分子生物学、生物物理学和工程方法，这些方法的结合将推动该领域的发展，并提供超越当前技术水平的强大工具。我们将首先通过比较神经元在机械上不同的定制环境中如何发育，确定环境必须具有哪些机械特性才能最佳地促进神经元的成熟和活动。然后，我们将使用一个微小的钢板弹簧（“悬臂”），用控制良好的力来推动和拉动神经元，这种力与细胞通常施加在其环境中的力一样小，同时测量流经这些神经元的电流。这些实验将揭示机械信号如何改变神经元的活动和成熟。最后，我们想了解神经元如何感知和翻译这些机械刺激。为此，我们将识别神经元中的力传感器，并研究它们的特定激活如何改变细胞功能。在这个项目中获得的知识不仅将阐明神经系统发展的一个新方面。机械信号也可能是理解不同发育障碍和神经系统疾病的缺失环节。我们的研究弥合了生命科学和物理科学之间的差距，可能最终导致我们治疗神经系统疾病患者的方式发生重大变化。

项目成果

Regenerative capacity of neural tissue scales with changes in tissue mechanics post injury

神经组织的再生能力随损伤后组织力学的变化而变化

• DOI: 10.1101/2022.12.12.517822
• 发表时间: 2022
• 作者: Carnicer-Lombarte A

Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons.

晚期内体充当 mRNA 翻译平台并维持轴突中的线粒体。

• DOI: 10.17863/cam.34436
• 发表时间: 2019
• 作者: Cioni J

Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons

• DOI: 10.1016/j.cell.2018.11.030
• 发表时间: 2019-01-10
• 期刊: CELL
• 影响因子: 64.5
• 作者: Cioni, Jean-Michel;Lin, Julie Qiaojin;Holt, Christine E.
• 通讯作者: Holt, Christine E.

Prevention of the foreign body response to implantable medical devices by inflammasome inhibition.

• DOI: 10.1073/pnas.2115857119
• 发表时间: 2022-03-22
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Barone DG;Carnicer-Lombarte A;Tourlomousis P;Hamilton RS;Prater M;Rutz AL;Dimov IB;Malliaras GG;Lacour SP;Robertson AAB;Franze K;Fawcett JW;Bryant CE
• 通讯作者: Bryant CE

Integrating Chemistry and Mechanics: The Forces Driving Axon Growth

化学与力学的结合：驱动轴突生长的力量

• DOI: 10.17863/cam.52630
• 发表时间: 2020
• 作者: Franze K