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.

人体细胞是高度组织和调节的，这种组织的任何变化都会对整个身体产生影响。近年来，越来越明显的是，细胞的一个关键部分是一种称为核层的结构，它围绕着细胞核。这种层结构由称为核纤层蛋白的蛋白质组成，对于维持正常的细胞结构和功能至关重要。事实上，核纤层蛋白充当维持核结构和核形状的支架。编码核纤层蛋白的 LMNA 基因的错误调节可能会通过突变发生，并导致各种人类疾病，包括肌肉疾病和称为早衰症的早衰综合症。这些综合征的共同特征是细胞核畸形，这是由于核纤层蛋白没有功能并且不能维持正常的核形态。对整个身体水平的影响主要出现在肌肉和心脏中，因为在这些器官中，细胞核结构是细胞在反复收缩中生存所必需的。因此，LMNA 基因缺陷的患者通常会因心脏病发作而过早死亡，因为他们的心肌细胞功能受到严重影响。有趣的是，LMNA 的失调也与正常衰老有关，与年轻人相比，老年人的细胞核似乎是畸形的。此外，核纤层蛋白在各种人类癌症中也有错误表达。一种模型认为，某些癌症中核纤层蛋白表达的变化可能导致细胞形态缺陷，从而导致癌症的侵袭性。 LMNA 失调与多种人类疾病以及正常衰老相关，这一事实引发了人们对拯救核纤层蛋白病中畸形细胞核、改善整体细胞健康和患者生存的强烈兴趣。不幸的是，目前这些疾病还没有治愈方法，可用的疗法主要是通过改善这些患者的症状来发挥作用。在本提案中，我们描述了我们计划如何表征一种新分子，该分子可挽救正常和过早衰老细胞系以及核纤层蛋白 A/C 耗尽细胞的形态缺陷。事实上，我们实验室最近的工作表明，这种分子可能会改善这些细胞的整体细胞适应性。因此，深入了解该分子的工作原理可以帮助我们了解核纤层蛋白病，并为我们提供一些关于如何挽救因 LMNA 失调引起的核形状缺陷的重要信息。为此，我们的目标是结合生化、遗传和细胞培养研究。我们相信这项工作可以提高我们对这些疾病的基础知识，也可以提出治疗这些疾病的新方法。此外，这项工作还可以为改善正常的与年龄相关的病理学开辟新的视角，这当然会对公共健康产生巨大影响。

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