Mechanisms of adhesion-dependent haematopoietic transdetermination

粘附依赖性造血转决定机制

• 批准号: MR/T028343/1
• 负责人: Nicholas Brown
• 金额: $ 73.28万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT028343%2F1
• 关键词: Mechanisms; adhesion; dependent; haematopoietic; transdetermination

Current treatments for leukemia and other blood disorders involve the transplantation of the stem cells that reside in our bone marrow and give rise to all types of blood cells. However, the availability of healthy stem cells for transplantation is limited, reducing the effectiveness of this treatment. If we are to increase the number of these cells that can be used for treatment, we need to discover more about how the stem cells arise and proliferate so that we can grow them in culture. Our research suggests that what may be preventing the successful culture of these cells at present is the absence of the appropriate mechanical signals from the surrounding environment. The tissues and organs in our body are made up of cells that need to stick to each other and the material that surrounds the cells, the extracellular matrix. By sticking to the extracellular matrix, the integrin receptors can sense when physical forces push or pull on cells. This helps explain how the physical surroundings of cells can affect what kind of cell they become. This proposal arose from our discovery that changes between types of cells within the blood of the model organism Drosophila are regulated by these mechanical pathways. This discovery provides us with a new easy way to discover how integrins can communicate to the nucleus to change cells from one type to another. The ability to grow large numbers of Drosophila and examine them for changes in their blood cell number means that we can identify the machinery of this pathway more easily than in mammals. Nonetheless, due to the high level of conservation of basic cellular mechanism between Drosophila and mammals, we expect that most of the machinery that we discover will have an equivalent in humans. Thus, our research will aid in treating diseases where cellular responses to mechanical signals goes awry. In addition to elucidating this integrin signalling pathway, we will also find out more about the process of changing cell fates, which will be of value for those aiming to reprogramme cells for therapeutic treatments.

目前对白血病和其他血液疾病的治疗涉及移植存在于骨髓中并产生所有类型血细胞的干细胞。然而，用于移植的健康干细胞的可用性有限，降低了这种治疗的有效性。如果我们要增加可用于治疗的细胞数量，我们需要更多地了解干细胞如何产生和增殖，以便我们可以在培养物中培养它们。我们的研究表明，目前阻碍这些细胞成功培养的原因可能是周围环境缺乏适当的机械信号。我们体内的组织和器官由需要相互粘附的细胞以及细胞周围的材料（细胞外基质）组成。通过粘附在细胞外基质上，整合素受体可以感知物理力何时推或拉细胞。这有助于解释细胞的物理环境如何影响它们变成什么样的细胞。这一提议源于我们的发现，即模式生物果蝇血液内细胞类型之间的变化受到这些机械途径的调节。这一发现为我们提供了一种新的简单方法来发现整合素如何与细胞核通讯以将细胞从一种类型改变为另一种类型。培养大量果蝇并检查它们血细胞数量的变化的能力意味着我们可以比哺乳动物更容易地识别该途径的机制。尽管如此，由于果蝇和哺乳动物之间基本细胞机制的高度保守性，我们预计我们发现的大多数机制在人类中也有类似的机制。因此，我们的研究将有助于治疗细胞对机械信号的反应出错的疾病。除了阐明这种整合素信号通路外，我们还将了解更多关于改变细胞命运的过程，这对于那些旨在重新编程细胞以进行治疗的人来说是有价值的。