Non-coding RNA In Stem Cell Biology

干细胞生物学中的非编码 RNA

• 批准号: 10197956
• 负责人: Josephina C van Wolfswinkel
• 金额: $ 41.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197956
• 关键词: Address; Adult; Affect; Aging; Animals; Binding; Biology; Cell Differentiation process; Cells; Chromatin; Congenital Abnormality; Embryonic Development; Failure; Fertility; Functional disorder; Gene Expression Regulation; Genome Stability; Germ Cells; Goals; In Vitro; Infertility; Malignant Neoplasms; Mediating; Molecular; Natural regeneration; Outcome; Pathway interactions; Planarians; Pluripotent Stem Cells; Population; Process; Proteins; RNA; Regulation; Role; Small RNA; Therapeutic; Untranslated RNA; in vivo; insight; pluripotency; stem cell biology; stem cell function; stem cells; targeted treatment

PROJECT SUMMARY Pluripotent stem cells are essential during early embryonic development, and hold great potential for therapeutic applications. In both cases, correct regulation of division and differentiation of these cells is crucial for a favorable outcome. Currently, there are major gaps in our understanding of how stem cells maintain their pluripotent state, or make the transition to differentiation. Several types of non-coding RNA are enriched in stem cells, and have been proposed to function in these regulatory processes, in particular by affecting the chromatin state of the cells. We will leverage a prolific population of adult pluripotent stem cells, the neoblasts of the planarian Schmidtea mediterranea, to address the role and mechanism of two types of non-coding RNA in in vivo stem cell biology. One branch of this project concerns the role of long non-coding RNAs (lncRNAs) in pluripotency and differentiation. Whereas many in vitro screens have suggested a role for lncRNAs in the regulation surrounding pluripotency, few cases of in vivo effects have been demonstrated. We will use an in vivo screen of planarian stem cell function to first identify functionally important lncRNAs, which will then be studied further mechanistically. This will allow us to focus our efforts on the most relevant examples of lncRNA- mediated stem cell regulation. The other branch of this project focuses on the role of PIWI-interacting RNAs (piRNAs), and their binding partners the PIWI proteins, in stem cell biology. These small RNAs are mostly known for their role in transposon silencing in the animal germline, but are also essential for stem cell function, especially in regenerating animals. We aim to determine what the basis for that requirement is, by determining which stages of stem cell biology are affected and what the consequences of failure of the piRNA pathway are. Furthermore several aspects of piRNA function are not easily addressed in germ cells, and we will use the planarian stem cells to further our understanding of those mechanistic aspects of piRNA biology. This project will provide new insights in non-coding RNA function and mechanism, and will have broad impact on our understanding of pluripotent stem cells and regulation of genomic stability in general. These insights are essential for the safe use of pluripotent cells in therapeutic applications, as well as for targeted treatment of conditions related dysfunction of endogenous stem cells including forms of infertility, birth defects, and aging. Furthermore, this project has relevance to conditions related to loss of cell identity, such as cancer.

项目总结 多能干细胞在早期胚胎发育中是必不可少的，并具有巨大的潜力 治疗应用。在这两种情况下，正确调控这些细胞的分裂和分化是至关重要的。 为了一个好的结果。目前，我们对干细胞如何维持其自身功能的理解存在重大差距。 多能状态，或向分化过渡。几种类型的非编码RNA富含 干细胞，并已被提议在这些调控过程中发挥作用，特别是通过影响 细胞的染色质状态。我们将利用大量的成体多能干细胞，即新生成体细胞 ，以解决两种非编码RNA的作用和机制 体内干细胞生物学。该项目的一个分支涉及长非编码RNA(LncRNAs)在 多能性和分化。尽管许多体外筛查表明lncRNAs在 关于多能性的调控，很少有体内效应被证明。我们将使用In 活体筛选脊椎动物干细胞功能，以首先识别功能上重要的lncRNAs，然后将 进一步机械地研究。这将使我们能够将我们的努力集中在lncRNA最相关的例子上- 介导的干细胞调节。该项目的另一个分支侧重于PIWI-相互作用的RNA的作用 (PiRNAs)及其结合伙伴PIWI蛋白，在干细胞生物学中。这些小RNA大多是 已知它们在动物生殖系转座子沉默中的作用，但对干细胞功能也是必不可少的， 尤其是在再生动物方面。我们的目标是确定这一要求的基础是什么，通过确定 干细胞生物学的哪些阶段受到影响，以及piRNA途径失败的后果是什么。 此外，在生殖细胞中不容易解决piRNA功能的几个方面，我们将使用 以进一步加深我们对piRNA生物学机制方面的理解。这个项目 将为非编码RNA的功能和机制提供新的见解，并将对我们的 总体上理解多能干细胞和基因组稳定性的调节。这些见解是 对于在治疗应用中安全使用多能细胞以及靶向治疗 与内源性干细胞功能障碍相关的条件，包括各种形式的不孕、出生缺陷和衰老。 此外，该项目与与细胞特性丧失相关的疾病相关，如癌症。