RUI: Physics of Cytoskeletal Organization in Neural Development

神经元是一种特殊的细胞，它传递电脉冲来控制心率、运动和高级大脑功能。一个复杂的神经元网络必须被适当地连接起来，以支持神经信号的空间和时间协调。在神经系统发育期间，神经元投射被称为轴突的纤维，这些纤维进行定向生长，形成与其他细胞的连接。一个被称为细胞骨架的动态蛋白质细丝网络促进了几种不同的机械功能，这些功能是轴突生长和发育的基础。这个项目的目标是应用计算模型来更好地理解细胞骨架中的力和运动如何调节神经发育和功能。该项目将在一所地区性综合性大学为不同的本科生群体提供培训，该大学大约95%是本科生，40%是第一代大学生，20%来自代表不足的少数民族。拟议的项目将建立在现有大学项目的影响之上，这些项目为来自代表性不足群体的学生提供研究机会。参与研究的本科生将有机会在暑假期间全职投入基础研究两个月(在资助期间有10-12名学生)。PI在物理学和生物学的边界上开发了几门新的课程，并开发和领导了跨学科的科学推广研讨会，旨在让低收入学生和其他在STEM领域中代表性不足的群体参与进来。PI将开发基于代理的计算模型，以研究神经元发育中的细胞骨架组织和机械功能，特别强调两个不同的神经元分区：(1)称为轴突的细长纤维，神经脉冲沿着它从细胞体传导到其他细胞；以及(2)轴突顶端的感觉运动结构，称为生长锥，它在发育或再生期间引导轴突生长。神经元的这些区域都含有许多相同的细胞骨架成分，但在每种情况下，这些分子成分都被重新用于不同的功能机械任务。将开发新的力学模型来研究在系统水平上由于部件的分子尺度相互作用而产生的紧急行为。这些模型将与实验同事密切合作进行测试和改进，模型预测将指导新实验的设计。该项目将解决有关神经元发育的基本机制问题，包括：在胚胎发育过程中，轴突如何沿着正确的方向生长，以便与其他细胞形成适当的连接？生长中的轴突如何发展和维持一个有组织的内部结构，能够促进神经递质和其他细胞囊泡在细胞内的定向运输？当轴突中的细胞骨架组织因疾病或损伤而被破坏时，什么机制可能有助于轴突修复？具体目标是：(1)调查细胞骨架细丝和生长锥底物黏附是如何协调的，以促进生长锥在化学指导下的转向；(2)调查发育中的轴突如何建立和维护对支持健康神经系统功能至关重要的极微管细丝的有序阵列。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Neurons are specialized cells that transmit electrical impulses to control heart rate, movement, and higher brain function. A complex network of neurons must be "wired" properly to support the spatial and temporal coordination of neural signals. During nervous system development, neurons project fibers called axons, which undergo directed growth to form connections with other cells. A network of dynamic protein filaments called the cytoskeleton facilitates several distinct mechanical functions underlying axonal outgrowth and development. The goal of this project is to apply computational models to better understand how forces and movements in the cytoskeleton mediate neural development and function. The project will provide training to a diverse group of undergraduate students at a regional comprehensive university that is approximately 95% undergraduate, 40% first-generation college students, and 20% from underrepresented minorities. The proposed project will build on the impact of existing university programs that provide research opportunities for students from underrepresented groups. Undergraduate students involved in the research will have the opportunity to become immersed in basic research full time for two months during the summer (10-12 students over the funding period). The PI has developed several novel courses at the boundary of physics and biology, and has developed and led interdisciplinary science outreach workshops designed to engage low-income students and other underrepresented groups in STEM fields.The PI will develop agent-based computational models to investigate cytoskeletal organization and mechanical function in developing neurons, with particular emphasis on two distinct neuronal compartments: (1) a slender fiber called an axon, along which neural impulses are conducted from the cell body to other cells; and (2) a sensory-motile structure at the tips of axons called a growth cone, which guides axonal outgrowth during development or regeneration. These regions of the neuron both contain many of the same cytoskeletal components, but in each context these molecular components are repurposed for functionally distinct mechanical tasks. Novel mechanical models will be developed to investigate emergent behavior that arises on a systems level from the molecular scale interaction of the parts. The models will be tested and refined in close collaboration with experimental colleagues, and model predictions will guide the design of new experiments. The project will address fundamental mechanistic questions about developing neurons, including: How do axons grow in the correct direction during embryogenesis to form the appropriate connections with other cells? How do growing axons develop and maintain an organized internal structure capable of facilitating directed intracellular transport of neurotransmitters and other cellular vesicles? When cytoskeletal organization in axons is disrupted due to disease or injury, what mechanisms may contribute to axonal repair? Specific objectives are: (1) Investigate how cytoskeletal filaments and growth cone substrate adhesion are coordinated to facilitate growth cone steering in response to chemical guidance cues; (2) Investigate how developing axons establish and maintain an organized array of polar microtubule filaments that is essential to support healthy nervous system function.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.