OPUS: MCS Functional solutions to cell-size evolution's geometry problem

一切生物都是由细胞组成的。有些生物，如细菌，只是一个单细胞。其他的，包括植物、动物和真菌，它们大到足以被人眼看到，可以由数万亿个细胞组成。组成身体不同部分的细胞彼此不同;皮肤细胞不同于心脏细胞，就像根细胞不同于叶细胞一样。尽管存在这些差异，但所有细胞都有很多共同点。构成生命基础的许多基本化学物质都发生在细胞内，使生物体能够生长、愈合并对环境做出反应。这种化学反应依赖于细胞内正确的分子相互接触，这需要数百万分子的复杂协调和运输。因此，这种分子协调和运输对生命至关重要，但细胞的一个影响其工作方式的主要特征-细胞本身的大小-仍然令人惊讶地研究不足。在自然界中，细胞以多种尺寸存在。较大的细胞从细胞表面到细胞核的距离较长，细胞核是细胞的控制中心。大细胞也有更多的内部细胞空间，这意味着任何两个潜在的相互作用分子可以彼此相距更远。了解细胞如何在不同大小下保持功能对于理解细胞如何协调和运输生命所需的无数分子的基本问题至关重要。这项研究将集中在10种蝾螈与一个非常广泛的大细胞大小。这些物种之间的比较将使研究人员能够实现以下目标：1）研究细胞大小的增加如何影响分子网络的功能（即基因调控网络、信号转导级联、代谢途径）通过增加分子间相互作用的随机性，2）研究细胞如何在面对增加的随机性、减少的表面积、以及伴随大细胞尺寸的体积增加，以及3）研究细胞水平上的这些变化如何影响代谢和胚胎发育的中心特征。这些目标将通过数学建模、比较RNA测序和细胞超微结构显微镜来实现。该研究团队由一名职业生涯中期的首席研究员和两名导师组成，其他科学家因其在数学建模和细胞大小方面的优势而被选中。这些实验室之间的协同作用将加强研究人员指导年轻科学家进行定量生物学研究的能力，并将促进科学家之间的新合作，以提高创造力和产出。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。

All living things are composed of cells. Some organisms, like bacteria, are just a single cell. Others, including the plants, animals, and fungi that are large enough to be seen by the human eye, can consist of trillions of cells. The cells that make up different parts of a body are different from one another; skin cells are different from heart cells, just as root cells are different from leaf cells. Despite these differences, however, all cells have a lot in common. Much of the fundamental chemistry that underlies life takes place within cells, allowing organisms to grow, heal, and respond to their environment. This chemistry depends on the right molecules coming into contact with one another inside the cell, which requires complex coordination and transportation of millions of molecules. This molecular coordination and transportation is thus critical for life, but a major feature of a cell that affects how it works - the size of the cell itself - remains surprisingly understudied. In nature, cells exist in many sizes. The larger ones have a longer distance to travel from the cell surface to the nucleus, which is the cell's control center. Large cells also have more internal cellular space, which means that any two potentially interacting molecules can be farther apart from one another. Understanding how cells maintain function at different sizes is critical for understanding the fundamental question of how cells coordinate and transport the countless molecules required for life. This study will focus on 10 species of salamanders with an exceptionally broad range of large cell sizes. Comparison across these species will allow the researchers to meet the following objectives: 1) study how increase in cell size impacts the function of molecular networks (i.e. gene regulatory networks, signal transduction cascades, metabolic pathways) through increased randomness in the interactions among molecules, 2) study how cells maintain function in the face of the increased randomness, decreased surface area, and increased volume that accompany large cell size, and 3) study how these changes at the cellular level impact the central traits of metabolism and embryonic development. These objectives will be met using mathematical modeling, comparative RNA sequencing, and cell ultrastructure microscopy. The research team consists of a mid-career principal investigator and two mentors, other scientists chosen for their strengths in mathematical modeling and cell size. Synergy across these labs will strengthen the investigator's ability to mentor young scientists in quantitative biology, and it will foster new collaborations among scientists to increase creativity and output.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.