马修·米勒博士.D., an assistant professor of biochemistry at University of Utah Health, was named as a 2022 Pew Scholar for his exploration of the cellular machines that help accurately divide and separate chromosomes during cell division. This work is critical as even the smallest errors in this process can have harmful consequences, 包括先天缺陷, 流产, 和癌症.
Miller is one of 22 scientists nationwide to receive the honor from the Pew Charitable Trusts. 的 皮尤生物医学学者项目 provides funding to early-career investigators of outstanding promise in science that is relevant to the advancement of human health.
米勒的研究集中在细胞分裂的一个关键阶段, 或有丝分裂, when protein-based machines called kinetochores help chromosomes correctly maneuver between parent and newly forming daughter cells. This process ensures that each cell receives a complete set of accurately replicated chromosomes.
Better understanding of how kinetochores work could lead to the development of genetic interventions or other treatments to reduce the risk of these disorders, 米勒说.
"Matt Miller is studying a truly fascinating and red-hot area of research," says Wes Sundquist, Ph.D., a former Pew Scholar and chair of the Department of Biochemistry at the University of Utah Health. 来解决这个问题, Matt uses an amazing multi-disciplinary combination of biochemistry, 生物物理学, 遗传学, and cell biology for which he is almost uniquely qualified owing to his wonderful breadth, 洞察力, 和创造力."
Understanding the process of chromosome separation during mitosis is a difficult challenge, 据米勒说. That’s because of its dynamic nature and the inability to precisely replicate the physical forces that regulate these activities in cells.
为了克服这个困难, Miller and his colleagues purify the protein machines involved and have developed techniques which allow them to reestablish their complex activities outside of a cell. This allows the researchers to experimentally control things such as applied physical force and ultimately understand how these factors carry out this process so reliably.
"Kinetochores are incredible protein machines,米勒说。. "的y move chromosomes within an ever-changing environment and are signaling hubs that help regulate the cell cycle. Biologists have been fascinated with this process for more than 100 years, yet we still don’t know how kinetochores achieve their remarkable feats."
事实上, 据米勒说, scientists still don’t have a complete "parts list" for the inner workings of kinetochores. It’s like knowing that an internal combustion engine makes a car run but not understanding that under the hood it is a collection of pistons, 火花塞, 以及其他重要的活动部件, 他说.
尽管如此, Miller and his colleagues are unraveling several key aspects of kinetochores and their role in cell division.
在细胞分裂期间, 细胞的遗传信息, 或DNA, 被包装成染色体的结构吗, which need to be copied and then partitioned equally between resulting daughter cells. 为了促进这个过程, kinetochores assemble on chromosomes and attach themselves to the mitotic spindle, 形成薄的分子机器, 被称为微管的线状链. 一旦他们这么做了, the duplicated chromosomes can move to opposite ends of the parent cell in preparation for cell division.
如果动点不能正常工作, 那么染色体就不会均匀分裂, 一个细胞最终可能会有太多或太少的分子. As a result, harmful imbalances and mutations can occur, 米勒说.
幸运的是，这类错误很少发生. So what keeps the chromosomes attached to the right microtubules? 米勒说，这一切都归结为紧张.
To accurately segregate replicated chromosomes to daughter cells, the chromosome must attach to microtubules from opposite sides of the cell. 相反方向的拉力产生张力, telling the cell it has the correct attachment configuration and can proceed with cell division. Miller and colleagues recently discovered that kinetochores have an intrinsic mechanism that "senses" this tension. 它的作用, 米勒说, 就像小孩子的手指夹, a simple puzzle that traps fingers in both ends of a small cylinder woven from bamboo. 的 harder a person tries to pull their fingers out, the tighter the device gets.
以同样的方式, the tension created by the force of opposing microtubule pulling keeps the chromosomes aligned properly. 当动丝点“感觉”到适当的张力时, they give the "go-ahead" signal and then move each of their chromosomes to opposite sides of the parent cell, 使细胞精确分裂.
使用一系列生物化学的尖端工具, 生物物理学, 基因编辑, Miller hopes to determine which "parts" of the protein machines are responsible for chromosomal attachment and segregation.
"We will then reconstitute the activities of these protein machines in a test tube to discover the mechanisms these protein machines use to carry out this process,米勒说。. "This work could lead to novel strategies for reducing the chromosomal segregation defects that give rise to many human diseases, including cancer and developmental disorders such as Down syndrome."
2022届皮尤奖学金获得者——都是职业生涯早期的人, junior faculty—will receive four years of funding to explore some of the most pressing questions in health and medicine. 的y were chosen from 197 applicants nominated by leading academic institutions and researchers across the United States.
####