The genetic basis and pathophysiology of bone marrow failure syndromes

骨髓衰竭综合征的遗传基础和病理生理学

• 批准号: MR/K000292/1
• 负责人: Inderjeet Dokal
• 金额: $ 68.77万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000292%2F1
• 关键词: genetic; basis; pathophysiology; bone; marrow

The bone marrow (BM) failure syndromes are a diverse group of life threatening disorders affecting children and adults. They are unified by the inability of the BM (the site of blood cell production) to make an adequate number of mature blood cells (red cells, white cells and platelets) and patients die prematurely from infection or bleeding if adequate treatment is not available. There are many different subtypes of BM failure. This includes the categories of dyskeratosis congenita (a severe inherited disorder in which many other systems of the body can be affected in addition to the blood system), idiopathic aplastic anaemia (the commonest type of BM failure whose cause remains unknown) and myelodysplasia (characterized by abnormalities in normal maturation of blood cells and where the underlying primary cause remains unknown). In approximately 40% of dyskeratosis congenita patients the genetic basis is unknown and in aplastic anaemia and myelodysplasia the primary cause remains unknown in over 80% of patients. The main aim of this research project is to determine the genetic basis and primary causes in the many uncharacterized cases of bone marrow failure. The experiments will involve undertaking genetic studies (including those based on the recently developed techniques of large scale gene sequencing so called next generation sequencing) in families with two or more affected cases with BM failure we have collected over the last 20 years. These studies will lead to the identification and characterization of new genes and cell pathways that are of fundamental importance. From the clinical perspective these studies will provide new diagnostic genetic tests and the possibility of developing new treatments that are highly desirable since prognosis remains unsatisfactory for many patients with bone marrow failure.

骨髓（BM）衰竭综合征是一组影响儿童和成人的危及生命的疾病。它们的统一是由于BM（血细胞产生部位）不能产生足够数量的成熟血细胞（红细胞、白色细胞和血小板），如果得不到适当的治疗，患者会因感染或出血而过早死亡。BM失效有许多不同的亚型。这包括先天性角化不良（一种严重的遗传性疾病，除血液系统外，身体的许多其他系统也会受到影响）、特发性再生障碍性贫血（最常见的BM衰竭类型，其原因尚不清楚）和骨髓增生异常（特征是血细胞正常成熟异常，其根本原因尚不清楚）。在大约40%的先天性角化不良患者中，遗传基础未知，在再生障碍性贫血和骨髓增生异常中，超过80%的患者的主要原因仍然未知。本研究项目的主要目的是确定遗传基础和骨髓衰竭的许多不明原因的情况下的主要原因。这些实验将涉及在我们在过去20年中收集的两个或更多受影响的BM失败病例的家庭中进行遗传研究（包括基于最近开发的大规模基因测序技术（称为下一代测序）的研究）。这些研究将导致新的基因和细胞通路的识别和表征，具有根本的重要性。从临床的角度来看，这些研究将提供新的诊断基因测试和开发新的治疗方法的可能性，这是非常可取的，因为预后仍然不令人满意的许多患者骨髓衰竭。