Chemical reversion of nuclear shape and other defects of Hutchinson Gilford Progeria Syndrome and Lamin A/C depleted cells

哈钦森·吉尔福德早衰综合症和核纤层蛋白 A/C 耗尽细胞的核形状和其他缺陷的化学逆转

• 批准号: MR/L019116/1
• 负责人: Stephen Jackson
• 金额: $ 39.69万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL019116%2F1
• 关键词: Chemical; reversion; nuclear; shape; other

Human cells are highly organised and regulated, and any change in this organisation can have an effect at the level of the entire body. In recent years, it has become evident that one crucial part of the cell is a structure called the nuclear lamina, which surrounds the cell nucleus. This lamina structure, which is made up of proteins called lamins, is crucial for maintaining normal cell structure and function. Indeed, lamins act as a scaffold for maintaining nuclear architecture and nuclear shape.Misregulation of the LMNA gene encoding for lamin proteins can occur through mutations, and leads to various human diseases, including muscular diseases and premature ageing syndromes called progerias. The common characteristic of these syndromes is misshapen cell nuclei due to the fact that the lamin proteins are not functional and cannot maintain normal nuclear morphology. The effects at the level of the entire body are predominantly found in the muscles and heart because, in these organs, the nuclear architecture is required for cells to survive repeated contractions. Consequently, patients with defects in the LMNA gene commonly die early from heart attacks because the function of their cardiac cells is strongly affected. Interestingly, misregulation of LMNA is also associated with normal ageing, and the nuclei of cells in old people appear to be misshapen compared to ones from young individuals.In addition, lamin proteins are also misexpressed in various human cancers. One model is that the change in lamin expression in some cancers could contribute to the cell morphology defects that account for the invasiveness of cancer. The fact that LMNA deregulation is associated with a broad range of human diseases, as well as with normal ageing, has triggered a strong interest in trying to rescue the misshapen nuclei in laminopathies, to improve global cellular fitness and patient survival. Unfortunately, currently there is no cure for these diseases, and the available therapies mainly act by improving the symptoms of these patients. In this proposal, we describe how we plan to characterize a new molecule that rescues the morphological defects of normal and premature ageing cell lines as well as Lamin A/C depleted cells. Indeed, recent work from our lab suggests that this molecule might improve the global cellular fitness of these cells. Thus, gaining insights into how this molecule works could help us understand the laminopathies and give us some important information about how to rescue the nuclear shape defects arising from LMNA misregulation. To this end, we aim to use a combination of biochemical, genetic and cell culture studies. We believe that this work could improve our fundamental knowledge of these diseases and could also suggest new ways of treating them. Moreover, this work could also open up new perspectives into improving normal age-related pathologies, which would of course have a great impact on public health.

人类细胞是高度组织和调节的，该组织的任何变化都可以在整个身体的水平上产生影响。近年来，很明显，细胞的一个关键部分是一种称为核薄片的结构，围绕细胞核。该薄片结构由称为lamins的蛋白质组成，对于维持正常的细胞结构和功能至关重要。实际上，lamins充当维持核结构和核形状的支架。对编码层粘连蛋白的LMNA基因可以通过突变发生，并导致各种人类疾病，包括肌肉疾病和称为POGERIAS的早熟衰老综合症。这些综合征的共同特征是畸形的细胞核，因为层粘连蛋白不起作用，无法维持正常的核形态。整个身体水平的影响主要在肌肉和心脏中发现，因为在这些器官中，细胞需要重复收缩需要核结构。因此，由于心脏细胞的功能受到严重影响，LMNA基因缺陷的患者通常会早日死于心脏病发作。有趣的是，LMNA的正常异常与正常衰老有关，与年轻人相比，老年人的细胞核似乎是畸形的。此外，加上层粘连蛋白在各种人类癌症中也受到了压抑。一种模型是，某些癌症中层粘连蛋白表达的变化可能导致解释癌症侵入性的细胞形态缺陷。 LMNA放松管制与广泛的人类疾病以及正常衰老有关，这引起了人们对试图挽救层状造成层核的浓厚兴趣，以改善全球细胞适应性和患者生存。不幸的是，目前无法治愈这些疾病，可用的疗法主要是通过改善这些患者的症状来起作用。在此提案中，我们描述了如何计划表征一种新分子，该分子挽救了正常和过早老化细胞系的形态缺陷以及层粘连蛋白A/C的枯细细胞。确实，我们实验室的最新工作表明，该分子可能会改善这些细胞的全球细胞适应性。因此，了解该分子的工作方式可以帮助我们理解层状病变，并为我们提供一些有关如何挽救LMNA失调引起的核形状缺陷的重要信息。为此，我们旨在结合生化，遗传和细胞培养研究。我们认为，这项工作可以提高我们对这些疾病的基本知识，还可以提出治疗它们的新方法。此外，这项工作还可以开辟新的观点，以改善正常的与年龄相关的病理，这当然会对公共卫生产生重大影响。

项目成果

Chemical inhibition of NAT10 corrects defects of laminopathic cells.

NAT10 的化学抑制可纠正核纤层蛋白病细胞的缺陷。

• DOI: 10.17863/cam.24738
• 发表时间: 2014
• 作者: Larrieu D

Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.

• DOI: 10.1111/acel.12506
• 发表时间: 2016-12
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Cobb AM;Larrieu D;Warren DT;Liu Y;Srivastava S;Smith AJO;Bowater RP;Jackson SP;Shanahan CM
• 通讯作者: Shanahan CM

[Chemical inhibition of NAT10 corrects defects of laminopathic cells].

[NAT10 的化学抑制可纠正核纤层蛋白病细胞的缺陷]。

• DOI: 10.1051/medsci/20143008010
• 发表时间: 2014
• 期刊: M/S
• 作者: Larrieu D

Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.

• DOI: 10.1038/s41467-018-03770-3
• 发表时间: 2018-04-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Balmus G;Larrieu D;Barros AC;Collins C;Abrudan M;Demir M;Geisler NJ;Lelliott CJ;White JK;Karp NA;Atkinson J;Kirton A;Jacobsen M;Clift D;Rodriguez R;Sanger Mouse Genetics Project;Adams DJ;Jackson SP
• 通讯作者: Jackson SP

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.

• DOI: 10.1136/jmedgenet-2016-104295
• 发表时间: 2017-03
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Bar DZ;Arlt MF;Brazier JF;Norris WE;Campbell SE;Chines P;Larrieu D;Jackson SP;Collins FS;Glover TW;Gordon LB
• 通讯作者: Gordon LB