Investigation of the processes determining mitochondrial fate in normal and malignant haematopoiesis

正常和恶性造血过程中决定线粒体命运的过程的研究

• 批准号: MR/T02934X/1
• 负责人: Stuart Rushworth
• 金额: $ 58.33万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT02934X%2F1
• 关键词: Investigation; processes; determining; mitochondrial; fate

Most people diagnosed with Acute Myeloid Leukaemia (AML) die of the disease because currently available chemotherapy targeting AML cells cannot eradicate the leukaemia from the bone marrow. In part, this is because the bone marrow environment promotes leukaemia growth and also provides protection from the drug treatment. It is envisaged that future treatment strategies targeting the environment and the tumour (the soil and the seed) will lead to improved outcomes for patients. This project looks to understand cancer specific protective functions of the bone marrow with a view to identify novel therapeutic strategies in the future. We have recently discovered that AML cells acquire their energy needs from the environment in which they proliferate. They do this by acquiring mitochondria (power plant of the cell) from other cells of the bone marrow. This supports the increased production of ATP (energy) which drives the survival and rapid proliferation of leukaemic cells. In this project we hypothesise that AML disposes of old mitochondria by excreting them from the cell in small parcels called vesicles. These vesicles are then eaten by cells known as macrophages which are the surveillance system of the bone marrow. The immune system is one of our natural defences against cancer and is known to form part of the process that can eradicate the disease. We propose in this project to understand how the vesicles from the leukaemia causes failure of the macrophages, and therefore if we could stop AML excreting the vesicles or prevent macrophages from eating them, this could identify new therapeutic targets to help treat this disease.

大多数被诊断患有急性髓性白血病（AML）的人死于这种疾病，因为目前可用的针对AML细胞的化疗不能从骨髓中根除白血病。在某种程度上，这是因为骨髓环境促进了白血病的生长，也提供了对药物治疗的保护。据设想，未来针对环境和肿瘤（土壤和种子）的治疗策略将改善患者的预后。该项目旨在了解骨髓的癌症特异性保护功能，以期在未来确定新的治疗策略。我们最近发现，AML细胞从它们增殖的环境中获得能量需求。他们通过从骨髓的其他细胞中获取线粒体（细胞的发电厂）来做到这一点。这支持ATP（能量）的增加产生，从而驱动白血病细胞的存活和快速增殖。在这个项目中，我们假设AML通过将旧线粒体从细胞中排泄到称为囊泡的小包裹中来处理旧线粒体。这些囊泡然后被称为巨噬细胞的细胞吃掉，巨噬细胞是骨髓的监视系统。免疫系统是我们对癌症的天然防御之一，并且已知是可以根除疾病的过程的一部分。在这个项目中，我们建议了解白血病的囊泡如何导致巨噬细胞的失败，因此，如果我们能够阻止AML分泌囊泡或防止巨噬细胞吃掉它们，这可以确定新的治疗靶点来帮助治疗这种疾病。

项目成果

Metabolic Regulation of Macrophages by SIRT1 Determines Activation During Cholestatic Liver Disease in Mice.

• DOI: 10.1016/j.jcmgh.2021.12.010
• 发表时间: 2022
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Isaacs-Ten A;Moreno-Gonzalez M;Bone C;Martens A;Bernuzzi F;Ludwig T;Hellmich C;Hiller K;Rushworth SA;Beraza N
• 通讯作者: Beraza N

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.

• DOI: 10.1172/jci153157
• 发表时间: 2022-03-01
• 期刊: The Journal of clinical investigation
• 作者: Moore JA;Mistry JJ;Hellmich C;Horton RH;Wojtowicz EE;Jibril A;Jefferson M;Wileman T;Beraza N;Bowles KM;Rushworth SA
• 通讯作者: Rushworth SA

Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion.

• DOI: 10.1186/s13059-023-02976-z
• 发表时间: 2023-06-27
• 期刊: Genome biology
• 影响因子: 12.3

Single-cell gene and isoform expression analysis reveals signatures of ageing in haematopoietic stem and progenitor cells.

• DOI: 10.1038/s42003-023-04936-6
• 发表时间: 2023-05-24
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Mincarelli, Laura;Uzun, Vladimir;Wright, David;Scoones, Anita;Rushworth, Stuart A.;Haerty, Wilfried;Macaulay, Iain C.
• 通讯作者: Macaulay, Iain C.