Necrosis regulation of bone marrow function

骨髓功能的坏死调节

• 批准号: 8633909
• 负责人: Sandra S Zinkel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633909
• 关键词: Accounting; Acute; Acute Myelocytic Leukemia; Acute leukemia; Affect; Allogeneic Bone Marrow Transplantation; Alzheimer' s Disease; Anemia; Apoptosis; Apoptosis Promoter; Apoptotic; Autoimmunity; Automobile Driving; BCL2 gene; Benzene; Birth; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Cancer Etiology; Cardiac; Cause of Death; Cell Death; Cell Death Signaling Process; Cell Proliferation; Cell physiology; Cells; Cessation of life; Cleaved cell; Clinical; Code; Complex; Data; Defect; Development; Disease; Dysmyelopoietic Syndromes; Dysplasia; Elderly; Environmental Exposure; Excision; Exposure to; Failure; Family; Family member; Frequencies; Genes; Health; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; Immune response; Incidence; Infection; Inflammatory Response; Injury; Knock-out; Knockout Mice; Lead; Light; Link; Malignant Neoplasms; Measures; Mediating; Medical; Mus; Mutagenesis; Myocardial Infarction; Natural regeneration; Necrosis; Outcome; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Persons; Pesticides; Phosphotransferases; Play; Population; Procedures; Receptor Activation; Receptor Signaling; Regulation; Regulatory Pathway; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Stem cells; Stimulus; Stress; Stroke; Syndrome; System; TNF gene; Testing; Therapeutic Intervention; Tissues; Toxin; Tumor Necrosis Factor-alpha; Veterans; agent orange; base; caspase-8; cell injury; chemotherapeutic agent; cytokine; disorder subtype; effective therapy; feeding; inhibitor/antagonist; insight; leukemia; mouse model; neoplasm registry; novel; outcome forecast; pathogen; prevent; programs; public health relevance; receptor; small molecule; stem; therapeutic target; tumor

Project summary: Dysregulated programmed cell death causes major health problems: too little death causes cancer and autoimmunity, and too much death causes bone marrow disorders such as Myelodysplastic Syndromes (MDS) and Alzheimer's disease. The major health problems of MDS arise from the death of critical cells resulting in cardiac stress and infection. In order to maintain hematopoietic function in the face of loss of critical hematopoietic progenitor cells, hematopoietic stem cells must actively cycle, exposing them to mutagenesis and perhaps driving the high rate at which MDS transforms to Acute Myelogenous Leukemia (AML). Understanding mechanisms of cell death regulation will lead to important insights into disease pathogenesis and transformation to malignancy, as well as new targets for therapeutic intervention. There are two major regulatory pathways used to induce cell death: apoptosis and necrosis. While the gene pathways and mechanisms driving apoptotic cell death have been extensively studied, those driving necrosis are less well understood. Moreover, necrosis but not apoptosis triggers an inflammatory response. Necrosis facilitates pathogen clearance during infection, but causes additional tissue damage in acute injuries such as stroke and myocardial infarction. Death receptor activation can induce both apoptotic and necrotic cell death. Exciting recent data indicates that components of the upstream apoptotic signaling pathway, including Caspase 8 and FLIP, inhibit necrosis, suggesting the presence of an early signaling switch to determine cell fate. Multiple lines of evidence placeBid as a component of the upstream death receptor-signaling pathway. We have developed a mouse model in which loss of Bid results in unrestrained bone marrow necrosis and bone marrow failure. Furthermore, we demonstrate that Rip1 kinase is elevated and Bid is decreased in primary MDS samples. Rip1 levels are highest in the RCMD subtype of MDS. Based on our preliminary findings, the central hypothesis of this proposal is that BH3-only Bid plays a critical role in hematopoietic homeostasis, by suppressing necrosis, perhaps by receiving and executing signals downstream of TNF¿ via Caspase 8 (extrinsic apoptosis) and Rip Kinases (necrosis).To test this central hypothesis, we propose to dissect the mechanism by which Bid inhibits necrosis (SA1) by defining Bid's interaction with pro-necrotic signaling complexes. We will further define Bid's impact on cell death signaling through the Rip kinases. To begin to investigate the impact of dysregulated necrotic signaling on bone marrow function (SA2), we will dissect the effect of Bid- mediated apoptosis and necrosis on hematopoietic stem and progenitor cell proliferation, differentiation, and regeneration in our mouse model that reveals unrestrained bone marrow necrosis. (SA3) will investigate necrosis signaling in primary human MDS bone marrow samples to correlate activation of necrosis and outcome in the subtypes of MDS. We will further evaluate the ability of inhibitors of necrosis to prevent bone marrow cell death in MDS samples.

项目摘要：程序性细胞死亡失调会导致重大健康问题：死亡太少会导致癌症和 自身免疫性，太多死亡会导致骨髓疾病，例如骨髓增生综合征（MDS）和阿尔茨海默氏症 疾病。 MD的主要健康问题是由于关键细胞的死亡导致心脏应激和感染。在 为了在临界造血祖细胞失去造血干细胞时保持造血功能 必须积极骑自行车，使它们暴露于诱变，并可能推动MDS转化为急性的高率 脊髓性白血病（AML）。了解细胞死亡调节的机制将导致对疾病的重要见解 发病机理和转化为恶性肿瘤，以及治疗干预的新目标。 有两种主要的调节途径用于诱导细胞死亡：凋亡和坏死。而基因途径和 驱动凋亡细胞死亡的机制已广泛研究，那些驾驶坏死的机制知之甚少。 此外，坏死而非凋亡会触发炎症反应。坏死促进了病原体清除 感染，但会导致急性损伤（例如中风和心肌梗塞）的其他组织损伤。 死亡受体激活可以诱导凋亡和坏死细胞死亡。令人兴奋的最近数据表明组件 上游凋亡信号通路，包括caspase 8和翻转，抑制坏死，表明存在 早期信号开关确定细胞命运。多种证据，被安慰为上游死亡的组成部分 接收器信号途径。我们已经开发了一个小鼠模型，其中出价的损失导致不受约束的骨髓 坏死和骨髓衰竭。此外，我们证明了RIP1激酶的升高，并且在初级中的出价降低 MDS样品。在MD的RCMD亚型中，RIP1水平最高。根据我们的初步发现，中心假设 该提议的是，仅BH3的出价在造血稳态中起着至关重要的作用，可以通过抑制坏死，也许是 通过caspase 8（外部细胞凋亡）和RIP激酶（坏死）接收和执行TNF¿下游的信号。 中心假设，我们建议通过定义投标与BID与BID相互作用的相互作用来剖析竞标抑制坏死的机制 促疾病信号传导复合物。我们将进一步定义出价对通过RIP激酶对细胞死亡信号传导的影响。开始 研究坏死信号失调对骨髓功能（SA2）的影响，我们将剖析投标的影响 造血茎和祖细胞增殖，分化和再生的介导凋亡和坏死 小鼠模型揭示了骨髓坏死。 （SA3）将研究原代人MDS中的坏死信号 骨髓样品与MDS亚型中坏死的激活相关。我们将进一步评估 坏死抑制剂预防MDS样品中骨髓细胞死亡的能力。