Clinical utility and biological impact of platelet-restricted clonal haematopoiesis

血小板限制性克隆造血的临床效用和生物学影响

• 批准号: MR/W02442X/1
• 负责人: Charlotte Elizabeth Lees
• 金额: $ 37.95万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW02442X%2F1
• 关键词: Clinical; utility; biological; impact; platelet

This project aims to understand the links between abnormally expanded blood stem cells, blood clots (venous thromboembolism) and ischemic heart disease. Blood stem cells have the capacity to self-renew and to develop into all the mature blood cells, such as white blood cells (that fight infection) and platelets (essential for blood clotting). As we age, DNA copying mistakes (mutations) are acquired, but most of these are inconsequential. However, sometimes these stem cells acquire mutations that give their progeny a survival advantage and their numbers expand. Such expanded populations are referred to as a clone; the process is termed clonal haematopoiesis. As you might expect, clonal haematopoiesis is found more frequently in the ageing population, in around 10-20% of people over 70 years. Clonal haematopoiesis is associated with a 10-fold increased risk of developing blood cancers. However, it has more recently been shown to be associated with a twofold increased risk of blood clots and heart disease. The underlying cause of this association between expanded clones and blood clots/heart disease is unknown, but it is thought to be entwined with the chronic inflammation which accompanies aging. It is thought that, due to abnormal immune responses, the expanded clone is associated with an inflammatory response which is known to contribute to these diseases. The detection of clonal haematopoiesis, a 'pre-cancer' state, in people with blood clots and heart disease could lead to new ways to prevent progression to blood cancer, as well as reduce risk of further blood clots or heart disease.There is evidence that many stem cells have offspring which only contribute to the platelet lineage, although they are still capable of becoming any type of blood cell. Furthermore, this 'platelet-bias' seems to occur more with advancing age. The standard techniques to detect stem cell clones look for specific mutations in mature white blood cells, but preliminary work in our lab shows that 10% of people over the age of 70 have clones detectable only in platelets as opposed to white blood cells; this is an entirely new finding. We don't yet know if these platelet-biased stem cell clones have links with blood clots and heart disease, as all of the evidence proving these links have used the standard white blood cell detection methods. Platelets are key to normal blood clotting and are implicated in inflammation and cancer, so we hypothesise that platelet-biased stem cell clones play an important role in this association. To investigate this, we aim:1. To determine if there is an association between platelet-biased clonal haematopoiesis and venous thromboembolism and heart disease. We will screen for the presence of platelet-biased CH in patients with blood clots and heart disease.2. To investigate the mechanisms by which platelet-biased clonal haematopoiesis drives increased blood clots and heart disease. This will include functional studies such as platelet activation studies, to determine if platelet-biased CH is associated with abnormal platelet activation. We will also analyse the bone marrow (where stem cells are made) of 5-10 patients to examine the cellular origins of these aberrant platelets. 3. To look for novel mutations that are specifically associated with platelet-biased clonal haematopoiesis, in case these are different to the mutations currently recognised to cause clonal haematopoiesis in white blood cells ie. the standard CH detection method.A key aim of the planned work is to develop expertise in clonal haematopoiesis which would support new CH clinics (already set up in the US but not the UK). Once detected, these patients could be counselled on how to reduce the risks associated with such clones. Through our work in understanding the mechanisms of these associations, we hope to identify targets for drug development to reduce the risk of diseases developing in these patients.

该项目旨在了解异常扩增的血液干细胞、血栓（静脉血栓栓塞）和缺血性心脏病之间的联系。造血干细胞具有自我更新和发育成所有成熟血细胞的能力，如白色血细胞（抗感染）和血小板（凝血所必需的）。随着年龄的增长，我们会获得DNA复制错误（突变），但其中大多数都是无关紧要的。然而，有时这些干细胞获得突变，使它们的后代具有生存优势，并且它们的数量增加。这种扩增的群体被称为克隆;这个过程被称为克隆造血。正如你所料，克隆造血在老龄化人群中更常见，70岁以上的人中约有10-20%。克隆性造血与发展血癌的风险增加10倍有关。然而，最近的研究表明，它与血液凝块和心脏病的风险增加一倍有关。扩增的克隆和血栓/心脏病之间的这种关联的根本原因尚不清楚，但它被认为是伴随着衰老的慢性炎症。据认为，由于异常的免疫应答，扩增的克隆与已知导致这些疾病的炎症应答相关。在患有血栓和心脏病的人中检测到克隆造血，一种“癌前”状态，可能会导致新的方法来预防血液癌症的进展，以及降低进一步血栓或心脏病的风险。有证据表明，许多干细胞的后代只有助于血小板谱系，尽管它们仍然能够成为任何类型的血细胞。此外，这种“血小板偏好”似乎随着年龄的增长而发生更多。检测干细胞克隆的标准技术是在成熟的白色血细胞中寻找特定的突变，但我们实验室的初步工作表明，70岁以上的人中有10%的人只在血小板中检测到克隆，而不是白色血细胞;这是一个全新的发现。我们还不知道这些偏向血小板的干细胞克隆是否与血栓和心脏病有关，因为所有证明这些联系的证据都使用了标准的白色血细胞检测方法。血小板是正常凝血的关键，并与炎症和癌症有关，因此我们假设血小板偏向干细胞克隆在这种关联中起重要作用。为了研究这一点，我们的目标是：1。确定血小板偏性克隆造血与静脉血栓栓塞和心脏病之间是否存在关联。我们将在有血栓和心脏病的患者中筛查血小板偏向性CH的存在。研究血小板偏好的克隆造血驱动血凝块增加和心脏病的机制。这将包括功能研究，例如血小板活化研究，以确定血小板偏向性CH是否与异常血小板活化相关。我们还将分析5-10名患者的骨髓（制造干细胞的地方），以检查这些异常血小板的细胞起源。3.寻找与血小板偏向性克隆造血特异性相关的新突变，如果这些突变与目前公认的导致白色血细胞中克隆造血的突变不同，即。标准的CH检测方法。计划工作的一个关键目标是发展克隆造血的专业知识，这将支持新的CH诊所（已经在美国建立，但不是英国）。一旦被发现，这些患者就可以被告知如何降低与这些克隆相关的风险。通过我们对这些关联机制的理解，我们希望确定药物开发的目标，以降低这些患者发生疾病的风险。