Project 3: Control of Differentiation and Dedifferentiation in Human Development

项目3：控制人类发展的分化和去分化

基本信息

批准号：
8520351
负责人：
William E Lowry
金额：
$ 32.91万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520351
关键词：
Adult Animal Experimentation Automobile Driving Bioinformatics Caenorhabditis elegans Cell Fate Control Cells Cellular biology Collaborations Core Facility Data Development Disease Disease model Embryo Epigenetic Process Family member Fetal Development Gene Expression Generations Genes Germ Layers Human Human Development In Vitro Knowledge Lead Life Malignant Neoplasms Mediator of activation protein Methods MicroRNAs Modification Molecular Pathway interactions Patients Play Pluripotent Stem Cells Pregnancy Process Publishing RNA Sequences Regenerative Medicine Regulation Reporter Role Somatic Cell Staging Stem cells Tissues Transplantation Work base cell type clinical application clinically relevant cohort early embryonic stage fetal genome-wide histone modification human embryonic stem cell human subject human tissue improved in vivo induced pluripotent stem cell inhibitor/antagonist loss of function model development novel pluripotency screening small molecule stem cell biology tool tumorigenesis

项目摘要

The promise of stem cell biology is predicated on the idea that these cells will be utilized in regenerative medicine and to model development and disease of tissues in vitro. While fantastic progress has been made in the generation of patient-specific stem cells through the use of reprogramming of somatic cells to a pluripotent state, little is known about the basic biology of these cells and whether they will be able to live up to their promise in regenerative medicine, development and disease. We have found that in vitro differentiation from hESCs and hiPSCs does not accurately reflect in vivo differentiation in human tissue. We have identified a molecular basis for this discrepancy and preliminary data suggest that in fact differentiation from human pluripotent stem cells could reflect human development but from a very early embryonic stage. We identified LIN28/let-7 as able to control human differentiation during early fetal development, in congruence with what has been shown for this circuit in C. Elegans. We propose to manipulate this important gene expression circuit to determine whether proper control of this circuit is vital to allow for maturation of human cells. This project will also develop tools that will allow for manipulation of this circuit and a simplified method for driving cellular maturation in vitro. Finally, we will use genome-wide approaches to understand how this circuit is normally regulated and whether it is representative of a cohort of co-regulated genes important for human development. This project will significantly contribute to our limited knowledge of human development, and the control of cell fate with human pluripotent stem cells. There will be no human subjects or animal experimentation with the proposed work.

干细胞生物学的希望是基于这些细胞将用于再生医学并在体外模拟组织的发育和疾病的想法。尽管通过将体细胞的重新编程到多能状态而产生的患者特异性干细胞已经取得了巨大进展，但这些细胞的基本生物学知之甚少在再生医学，发育和疾病中。我们发现，从hESC和HIPSC的体外分化并不能准确反映人体组织中的体内分化。我们已经确定了这种差异的分子基础，并且初步数据表明，实际上与人多能干细胞的分化可以反映人类的发育，但要从非常早期的胚胎阶段。我们确定LIN28/Let-7是能够在早期胎儿发育过程中控制人类分化的，这与秀丽隐杆线虫中该电路所显示的内容一致。我们建议操纵这一重要的基因表达回路，以确定对该电路的适当控制对于允许人类细胞的成熟至关重要。该项目还将开发工具，这些工具将允许操纵该电路，并简化体外驱动细胞成熟的方法。最后，我们将使用全基因组的方法来了解该电路通常如何调节，以及它是否代表了对人类发育重要的共同调节基因的队列。该项目将显着有助于我们对人类发展的有限了解，并通过人类多能干细胞控制细胞命运。拟议的工作将不会进行人类的受试者或动物实验。