Tissue Engineered Model of Aging to Study the Role of Cellular Interdependence in Failing Tissues

虽然已经取得了进展，但衰老仍然是现代生物学中未解决的问题。已经确定了许多导致细胞损伤的机制，但生物体，即，活着的动物和植物，大概不是因为它们耗尽了细胞，而是因为更大规模的失败。细胞的衰竭会扩散到组织、器官，最终导致机体的衰竭。 该项目的重点是这种有序崩溃的第一个中间步骤：从细胞到组织的失败传播。为此，该项目将从理论上和实验上建立衰老组织中细胞之间复杂相互作用的作用，使用组织工程策略独立控制年龄和细胞相互作用。 实验将辅以数学模型和计算机模拟，这些模型和计算机模拟将输出死亡率曲线（随年龄增长的死亡概率图）和这些组织的预期寿命。此外，该项目将能够量化细胞尺度老化过程与大尺度相互作用效应引起的老化过程相比的相对重要性。从更广泛的影响来看，老龄化影响到每个人。随着预期寿命的稳步增长，迫切需要更好地了解衰老的基本原理，以找到减少与年龄有关的疾病的方法。该项目将为科学和医学界提供关于衰老所涉及的多个尺度的新观点，为延迟或逆转衰老的新方法铺平道路，并帮助实现更健康的老年。研究结果将传播给广大受众，从中学到本科生和研究生，以及当地社区，特别强调在STEM领域代表性不足的群体。活动包括为中学女生举办的讲习班，为高中生举办的区域科学博览会项目以及在当地医疗中心举办的研讨会。虽然存在一些关于细胞损伤的理论，但对微观故障如何级联到组织，器官和最终生物体的宏观尺度故障知之甚少。该项目的目标是通过理论和实验建立衰老组织中细胞之间复杂的相互依赖和相互作用的作用，将微观细胞失效与宏观衰老表现联系起来。基于来自研究者实验室的强有力的初步数据，假设衰老（定义为随实际年龄增加的死亡概率）是由于通过相互依赖的细胞网络级联的故障，而不是一系列孤立的细胞故障。为了验证这一假设，本项目的目的是：1）制造由不同密度的（老年人和年轻人）心脏组织的单个和多个细胞类型2）在有和没有氧化应激的情况下使组织老化一个月，同时测量组织和细胞内的群体的存活统计;（3）利用详细的分析理论对相互作用的作用进行推断。具体而言，计算模型研究的空间相互依存网络的边缘权重由扩散方程和一级反应动力学。这些节点的故障是随机的，取决于它们与其他节点的相互作用，就像一个扩散。计算框架将为拟议的实验生成可检验的假设，作为回报，实验测量将约束模型参数。项目发现有可能通过引入一种全新的观点来改变衰老研究，即衰老是任何（生命或非生命）系统的普遍属性，该系统具有足够数量的组件，这些组件相互依赖以执行其微观功能。此外，这一观点第一次使量化和模拟老化进程的能力成为可能，并给出了一定的相互依赖网络结构，以预测相互依赖的系统应如何以及何时发生灾难性崩溃。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。

Though progress has been made, aging remains an unsolved problem in modern biology. A number of mechanisms that lead to cell damage have been identified, but organisms, i.e., living animals and plants, presumably die not because they run out of cells, but because of failures of much larger scale. Cellular failures spread into failure of tissues, organs and ultimately the organism. This project focuses on the first intermediate step of this ordered collapse: the spread of failure from cells to tissues. To this end, the project will theoretically and experimentally establish the role of complex interactions between cells in aging tissues, using tissue engineering strategies to independently control both age and cell interactions. Experiments will be supplemented by mathematical models and computer simulations that will output mortality curves (plots of probability of death with increasing age) and life expectancies of these tissues. Furthermore, the project will be able to quantify the relative importance of cellular scale aging processes compared to those stemming from larger scale interaction effects. In view of broader impacts, aging affects everyone. With steadily increasing life expectancy, there is an immediate need to better understand principles underlying aging to find ways to decrease age-related diseases. This project will offer a fresh view to the scientific and medical community on the multiple scales involved in aging, paving the way for new approaches to delay or reverse aging and help attain healthier old ages. The research findings will be disseminated to a broad audience, from middle school to undergraduate and graduate students, and to the local community, with specific emphasis on underrepresented groups in STEM fields. Activities include workshops for middle school girls, regional science fair projects for high school students and seminars at a local medical center.Although there exist a number of theories on cell damage, very little is known about how microscopic failures cascade to macro scale failure of tissues, organs and ultimately the organism. The goal of this project is to bridge microscopic cell failure to macroscopic manifestations of aging, by theoretically and experimentally establishing the role of complex interdependence and interactions between cells in aging tissues. Based on strong preliminary data from the investigators' labs, it is hypothesized that aging, defined in terms of an increased probability of death with chronological age, is due to failures cascading through an interdependent network of cells, rather than a series of isolated cell failures. To test this hypothesis, the aims of this project are to 1) Fabricate 3D engineered heart tissues consisting of varying densities of (aged and young) single and multiple cell types of the heart tissue (cardiac fibroblasts, cardiomyocytes and endothelial cells); 2) Age the tissue for a month, both with and without oxidative stress, while measuring the survival statistics of a population of tissues and cells within; and 3) Make inferences regarding the role of interactions using a detailed analytical theory. Specifically, the computational model studies spatial interdependence networks whose edge weights are determined by the diffusion equation and first order reaction kinetics. The nodes fail stochastically depending on their interaction with others, in a percolation-like spread. The computational framework will generate testable hypotheses for the proposed experiments, and in return, experimental measurements will constrain the model parameters. Project findings have the potential to transform aging research by introducing an entirely new view that aging is a universal attribute of any (living or non-living) system that has a sufficient number of components that strongly depend on one other to carry out their microscopic functions. Furthermore, this view enables, for the first time, the ability to quantify and simulate the progression of aging, given a certain interdependence network structure to predict how and when an interdependent system should be expected to catastrophically collapse.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.