Mechanisms and determinants of dynamic gene regulation during development and cellular differentiation

发育和细胞分化过程中动态基因调控的机制和决定因素

• 批准号: 10680595
• 负责人: Sebastian Pott
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680595
• 关键词: Biological Models; Biomedical Research; Cells; Code; Development; Disease; Epigenetic Process; Gene Expression Regulation; Genetic; Genetic Transcription; Genome; Genomics; Heterogeneity; Homeostasis; Human; Human Genome; Individual; Malignant Neoplasms; Metabolic Diseases; Organism; Organoids; Pathology; Process; Regulator Genes; Sampling; Specific qualifier value; Stimulus; Technology; cell type; chronic inflammatory disease; genetic manipulation; human disease; human tissue; in vitro Model; induced pluripotent stem cell; multiple omics; pathogenic microbe; response; tool

PROJECT SUMMARY The human genome encodes information that specifies the development of an entire organism comprising at least 10 trillion cells and more than 200 different cell types. The genome also contains the information to direct appropriate responses to a host of environmental stimuli to maintain homeostasis and respond to challenges, e.g. from microbial pathogens. Changes to this code or dysregulation of its interpretation underlie almost all human diseases, including chronic inflammatory diseases, metabolic disorders, and cancer. Obtaining mechanistic and quantitative understanding of gene regulation in individual cells is a crucial prerequisite for a better understanding, and ultimately treatment, of diseases. Studying gene regulatory processes in human tissues has been challenging because of their cellular heterogeneity and because most human samples are not accessible to longitudinal observations and direct perturbations. However, the advent of single cell genomic technologies, the development of human iPSC and organoid-based in vitro model systems, and the availability of powerful tools for genetic perturbations have the potential to overcome these challenges and to revolutionize biomedical research. In this proposal we combine the development of single- cell multiomic tools that accurately profile multiple regulatory features within single cells or molecules with mechanistic and disease-focused studies to understand how genetic and environmental perturbations of gene regulatory processes disrupt cellular differentiation and underlie pathologies.

项目摘要 人类基因组编码的信息指定了整个生物体的发育， 至少10万亿个细胞和200多种不同的细胞类型。基因组还包含了指导 对环境刺激的适当反应，以维持稳态并应对挑战， 例如从微生物病原体。这一准则的改变或对其解释的失调几乎是所有 人类疾病，包括慢性炎性疾病、代谢紊乱和癌症。获得 对单个细胞中基因调控的机制和定量理解是一个至关重要的 这是更好地了解并最终治疗疾病的先决条件。研究基因调控 由于其细胞异质性，并且由于大多数人的免疫缺陷， 人体样本无法进行纵向观测和直接扰动。然而， 单细胞基因组技术，人类iPSC和基于类器官的体外模型的开发 系统，以及遗传扰动的强大工具的可用性有可能克服这些问题。 挑战和革命性的生物医学研究。在这个建议中，我们联合收割机的发展， 细胞多组学工具，其准确地描绘单细胞或分子内的多种调控特征， 机制和疾病为重点的研究，以了解基因的遗传和环境扰动如何 调节过程破坏细胞分化并成为病理学的基础。