Collaborative Research: Mechanical Regulation of Cell Death

一个人要健康，细胞必须被创造出来，在适当的时候，有时会死亡。 有很多疾病是由细胞没有在正确的时间死亡引起的。 细胞的死亡被施加到组织上并在组织内产生的物理力改变。然而，人们对这些力如何改变细胞死亡的时间或速度知之甚少。细胞的内部分子在细胞之间产生和携带负荷。这项研究的目的是确定肌动蛋白分子的具体作用，以及控制肌动蛋白的途径，在细胞死亡的机械调节。这项工作将确定可以通过药物操纵的小分子和大分子，以改变负荷如何调节许多疾病中的细胞死亡，包括肿瘤，心脏病，关节炎和骨质疏松症。该项目将支持一名博士生和六名本科生研究人员（REU）在我们的校园之间进行指导。作为该项目的一部分，这些学生研究人员指导来自服务水平低下的中学的女生参加为期一周的项目，重点是通过独立的小型研究项目获得信心。该项目将推进对单细胞和多细胞组织背景下如何产生力的基本理解。它将阐明机械力如何调节细胞死亡。细胞力和肌动蛋白动力学在细胞凋亡中的作用将在多个尺度上进行研究;在细胞群中，在单个细胞中，以及在分子信号传导尺度上。整体方法是基于力学的，并结合了相互通知的实验和计算模型，以获得细胞和组织内力分布的准确地图。这项工作将确定如何机械力，肌动蛋白细胞骨架，以及相关的信号通路共同调节细胞凋亡。定量了解诱导细胞凋亡的机械信号和传递这些信号的机制对于理解涉及细胞死亡控制不当的各种疾病状态的潜在病理生理学是至关重要的。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

For a person to be healthy, cells must be created and, at the right time, sometimes die. There are many diseases that are caused by cells that don't die at the correct time. The death of cells is changed by physical forces applied to and generated within tissues. However, relatively little is known about how the forces change the timing or speed of cell death. The interior molecules of a cell create and carry loads between cells. The goal of this research is to determine the specific role of the molecule actin, and the pathways that control actin, in the mechanical regulation of cell death. The work will identify small and large size molecules that can be manipulated by drugs to change how loads regulate cell death in many diseases, including tumors, heart disease, arthritis and osteoporosis. The project will support training of a doctoral student and six undergraduate researchers (REU) mentored between our campuses. As part of the program, these student researchers mentor girls from underserved middle-schools in a one-week program focused on gaining confidence through independent mini-research projects.This project will advance the fundamental understanding of how forces are generated by single cells and within the context of multicellular tissues. It will elucidate how mechanical forces regulate cell death. The role of cell forces and actin dynamics in apoptosis will be studied at multiple scales; in clusters of cells, in individual cells, and at the molecular signaling scale. The overall approach is mechanics-based and combines experimental and computational models that inform each other to obtain accurate maps of the force distribution within cells and tissues. The work will identify how mechanical forces, the actin cytoskeleton, and relevant signaling pathways collectively regulate apoptosis. Quantitative knowledge of the mechanical signals that induce apoptosis and the mechanisms transmitting these signals is fundamental for understanding the underlying pathophysiology of various disease states that involve improper control of cell death.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.