Regulation of Cellular Plasticity

细胞可塑性的调节

• 批准号: RGPIN-2020-05214
• 负责人: Bonni, Shirin
• 金额: $ 2.33万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744251
• 关键词: Regulation; Cellular; Plasticity

Cellular plasticity, defined as the ability of cells change their phenotype in a reversible manner, is critical for the developing and adult organism. My research program is interested in understanding the regulatory mechanism that control cellular plasticity. A cellular process called epithelial-mesenchymal transition (EMT) is associated with cellular plasticity. EMT is a fundamental in development. Cells undergoing EMT change from being epithelial nature, where there are cell-cell contact, apical-basal polarity, and presence of epithelial marker like E-cadherin, to becoming fibroblastic in terms of shape and expression of markers and the change of actin from being cortical to stress fiber like. Cells undergoing EMT can revert back to acquire all or part of the epithelial phenotypes. A major question in the field is the mechanisms that regulate the ability of cells to undergo EMT. It is well established that signaling proteins like TGFß can induce EMT with relevance for development and homeostasis. Development of the mammary glands occurs largely postnatally. EMT has been suggested to contribute the branching morphogenesis. We use mammary epithelial cells to uncover the regulatory mechanisms controlling EMT. We have discovered that the small ubiquitin like modifier (SUMO) system regulate EMT-associated cellular plasticity through targeting specific substrates for sumoylation. Our findings have also raised the key question of the molecular mechanisms by which the SUMO-dependent pathways regulate EMT-associated cellular phenotypes. Chromatin compactness and regulation (epigenetics) play key roles in controlling expression of genes that ultimately may manifest as specific phenotype, eg as in EMT. However, how these epigenetic processes are modulated to control cell phenotype remain poorly understood. The proposed research described in this application will investigate the role of specific sumo pathways that by promoting sumoylation of the transcriptional regulator SnoN which in turn suppress EMT in mammary epithelial cells grown in a three-dimensional manner. Based on preliminary data, we propose to study the link between SnoN and specific chromatin remodelers to regulate the cellular plastic process of EMT. This research will add new insights into how EMT and cellular plasticity are regulated.

细胞可塑性，定义为细胞以可逆方式改变其表型的能力，对于发育和成年生物体至关重要。我的研究项目是了解控制细胞可塑性的调节机制。上皮-间充质转化（EMT）是一个细胞过程，与细胞可塑性有关。EMT是发展的基础。经历EMT的细胞从上皮性质（其中存在细胞-细胞接触、顶端-基底极性和上皮标志物如E-钙粘蛋白的存在）变为成纤维细胞（就标志物的形状和表达而言）和肌动蛋白从皮质变为应力纤维样。经历EMT的细胞可以恢复以获得全部或部分上皮表型。该领域的一个主要问题是调节细胞进行EMT的能力的机制。已经确定，信号蛋白如TGF β 1可以诱导与发育和稳态相关的EMT。乳腺的发育主要发生在出生后。EMT已被认为有助于分支形态建成。我们使用乳腺上皮细胞来揭示控制EMT的调节机制。我们已经发现小泛素样修饰物（SUMO）系统通过靶向特定的SUMO化底物来调节EMT相关的细胞可塑性。我们的研究结果也提出了SUMO依赖性途径调节EMT相关细胞表型的分子机制的关键问题。染色质紧密性和调节（表观遗传学）在控制基因表达中发挥关键作用，最终可能表现为特定的表型，例如在EMT中。然而，这些表观遗传过程是如何调制控制细胞表型仍然知之甚少。本申请中描述的拟议研究将调查特定sumo途径的作用，该途径通过促进转录调节因子SnoN的sumo化，进而抑制以三维方式生长的乳腺上皮细胞中的EMT。基于初步的数据，我们建议研究SnoN和特定的染色质重塑之间的联系，以调节EMT的细胞可塑性过程。这项研究将为EMT和细胞可塑性如何调节提供新的见解。