Dissecting the regulatory roles of 14-3-3zeta on the adipogenic transcriptional program

剖析 14-3-3zeta 对脂肪形成转录程序的调节作用

• 批准号: RGPIN-2017-05209
• 负责人: Lim, Gareth
• 金额: $ 1.89万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=657621
• 关键词: Dissecting; regulatory; roles; 14; 3zeta

The growth of a fat cell, or adipocyte, is a complex process that involves a complicated network of proteins. These proteins need to be in the right place and time, but it is not well known what factors within the fat cell coordinate the actions of these proteins. Molecular scaffolds are possible candidates because of their abilities to help proteins connect with one another and to keep them in different areas of a cell. Previously, I have found that one molecular scaffold called 14-3-3ζ was required for fat cell development. Mice that did not have 14-3-3ζ, were very lean and had less fat. On the other hand, mice that had increased amounts of 14-3-3ζ in every cell became fatter when fed a diet rich in fat. Despite these roles in controlling the amount of fat, the specific mechanisms of how 14-3-3ζ controls fat cell growth requires further investigation. 14-3-3ζ and other members of this protein family are unique because they are able to connect with a diverse group of proteins, and this suggests that they may control the growth of a fat cell through multiple pathways and mechanisms. Therefore, the goals of this proposal are to explore and define these pathways in order to better understand how fat cells are formed. To better understand the role of 14-3-3ζ in the growth of a fat cell, a new cell model will be made with CRISPR-Cas9 technology to insert a modified version of 14-3-3ζ in the cell. This will allow for the simple and clean extraction of 14-3-3ζ in order to see what types of genes it may control, as well as the identifies of proteins that it may touch, connect, and influence. I anticipate that these proposed studies will identify new players that are involved in the growth of fat cells. Aside from other researchers who study fat cell development, this work has the potential to be applied to other cell types across different fields of study. Results from the proposed studies will increase our understanding of how different types of cell develop and will reveal how the actions of proteins are coordinated in a cell. Furthermore, knowledge gained from these studies may be applied to the development of new therapies that are influenced by increases in body fat, such as obesity, heart disease, and diabetes.

脂肪细胞或脂肪细胞的生长是一个复杂的过程，涉及复杂的蛋白质网络。这些蛋白质需要在正确的地点和时间出现，但目前尚不清楚脂肪细胞内的哪些因素协调这些蛋白质的作用。分子支架是可能的候选者，因为它们能够帮助蛋白质彼此连接并将它们保持在细胞的不同区域。此前，我发现脂肪细胞发育需要一种名为14-3-3 z 的分子支架。没有 14-3-3 z 的小鼠非常瘦，脂肪含量也较少。另一方面，每个细胞中 14-3-3 z 含量增加的小鼠在喂食富含脂肪的饮食后会变得更胖。尽管在控制脂肪量方面发挥了这些作用，但 14-3-3ze 控制脂肪细胞生长的具体机制还需要进一步研究。 14-3-3 z 和该蛋白质家族的其他成员是独特的，因为它们能够与不同的蛋白质组连接，这表明它们可以通过多种途径和机制控制脂肪细胞的生长。因此，该提案的目标是探索和定义这些途径，以便更好地了解脂肪细胞是如何形成的。为了更好地了解14-3-3ζ在脂肪细胞生长中的作用，将利用CRISPR-Cas9技术制作新的细胞模型，在细胞中插入14-3-3ζ的修改版本。这将允许简单、干净地提取 14-3-3 z，以便了解它可能控制哪些类型的基因，以及它可能接触、连接和影响的蛋白质的识别。我预计这些拟议的研究将确定参与脂肪细胞生长的新参与者。除了研究脂肪细胞发育的其他研究人员之外，这项工作还有可能应用于不同研究领域的其他细胞类型。拟议研究的结果将增加我们对不同类型细胞如何发育的理解，并将揭示蛋白质的作用如何在细胞中协调。此外，从这些研究中获得的知识可以应用于开发受身体脂肪增加影响的新疗法，例如肥胖、心脏病和糖尿病。