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

人类细胞是高度有组织和受监管的，这种组织的任何变化都可以在整个身体的层面上产生影响。近年来，很明显，细胞的一个重要部分是一种名为核层的结构，它包围着细胞核。这种片层结构由称为片层蛋白的蛋白质组成，对维持正常的细胞结构和功能至关重要。事实上，层粘连蛋白作为维持核结构和核形状的支架。层粘连蛋白编码的LMNA基因的错误调节可能通过突变发生，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征。这些综合征的共同特征是细胞核畸形，这是由于层蛋白不起作用，不能维持正常的核形态。在整个身体层面上的影响主要在肌肉和心脏中发现，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会受到严重影响。有趣的是，LMNA的错误调节也与正常衰老有关，与年轻人相比，老年人的细胞核似乎畸形。此外，层蛋白也在各种人类癌症中错误表达。一种模型是，某些癌症中层粘连蛋白表达的变化可能是导致癌症侵袭性的细胞形态缺陷的原因之一。事实上，LMNA的解除管制与一系列人类疾病以及正常衰老有关，这引发了人们对试图挽救椎板病中畸形的核，以改善全球细胞健康和患者生存的强烈兴趣。不幸的是，目前还没有治愈这些疾病的方法，现有的治疗方法主要是通过改善这些患者的症状来起作用的。在这项提案中，我们描述了我们计划如何表征一种新的分子，该分子可以修复正常和早衰细胞系以及Lamin 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LMNA分子的作用机制可以帮助我们理解椎板病变，并为我们提供一些重要的信息，帮助我们挽救由于LMNA调控不当而产生的核形状缺陷。为此，我们的目标是结合生物化学、遗传学和细胞培养研究。我们相信，这项工作可以提高我们对这些疾病的基本知识，并可能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开辟新的视角，这当然会对公共健康产生巨大影响。

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.