Determinants of Cell State Reprogramming

细胞状态重编程的决定因素

• 批准号: 10406224
• 负责人: Gary Chung Hon
• 金额: $ 46.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406224
• 关键词: Address; Biological Process; Biomedical Research; Cells; Couples; Engineering; Epigenetic Process; Failure; Foundations; Genetic; Germ Cells; Goals; Health; Human; Individual; Knowledge; Learning; Mission; Molecular; Molecular Genetics; Phenotype; Process; Public Health; Regenerative Medicine; Research; United States National Institutes of Health; catalyst; cell type; epigenome; experimental study; improved; innovation; insight; success; transcription factor; transcriptome

Determinants of cell state reprogramming PROJECT SUMMARY Forced expression of transcription factors (TFs) can reprogram cell state. The discovery of direct reprogramming has been a catalyst for our understanding of the molecular and genetic drivers of cell state. However, despite its successes, only a handful of successful reprogramming cocktails have been identified, the conversion process is often inefficient, and the mechanistic reasons for reprogramming failure are often unclear. Thus, a key obstacle to further progress is our incomplete understanding of the determinants and mechanisms of cell state conversion. Our long term goal is to understand the genetic and molecular basis of cell state, which has important implications for synthetic control of cell state for regenerative medicine. Towards this goal, the objective of this proposal is to elucidate the molecular and cellular determinants of cell state reprogramming. Specifically, we seek to address several fundamental gaps in knowledge on cell state reprogramming with three central research directions: 1) Epigenetic determinants of cellular reprogramming, 2) Genetic and temporal determinants of cellular differentiation, and 3) Initial cell state determinants on reprogramming. This scope is made possible by our innovative platform that couples multifactorial, pooled perturbation with multidimensional readouts for each cell spanning perturbations (induced TFs), mechanisms (epigenome), and phenotypes (transcriptome). By tracing thousands of individual cells on their path to reprogramming across a multitude of distinct perturbations, our high throughput functional experiments will reveal insights and suggest mechanisms for the determinants of reprogramming. Our rationale is that learning these fundamental rules of reprogramming will improve our understanding of the molecular basis of cell state and enable improved approaches to manipulate it.

细胞状态重编程的决定因素 项目摘要 转录因子（TF）的强制表达可以重新编程细胞状态。直接重编程的发现 一直是我们理解细胞状态的分子和遗传驱动因素的催化剂。然而，尽管其 成功，只有少数成功的重编程鸡尾酒已被确定，转换过程 通常是低效的，并且重编程失败的机械原因通常不清楚。因此，一个关键障碍 进一步的进展是我们对细胞状态转换的决定因素和机制的不完全理解。 我们的长期目标是了解细胞状态的遗传和分子基础，这具有重要意义 用于再生医学的细胞状态的综合控制。为实现这一目标，本提案的目标是 阐明细胞状态重编程的分子和细胞决定因素。具体而言，我们寻求解决 关于细胞状态重编程知识的几个基本空白，有三个中心研究方向：1） 细胞重编程的表观遗传决定因素，2）细胞重编程的遗传和时间决定因素 分化，和3）重编程的初始细胞状态决定因素。这个范围是由我们的 创新平台，将多因素合并扰动与每个细胞的多维读数相结合 跨越扰动（诱导的TF）、机制（表观基因组）和表型（转录组）。通过追踪 成千上万的个体细胞在经历了众多不同的扰动后重新编程，我们的高 通量功能实验将揭示见解，并提出机制的决定因素， 重新编程我们的理论基础是，学习这些重新编程的基本规则将改善我们的 了解细胞状态的分子基础，并使改进的方法来操纵它。