Necrosis regulation of bone marrow function

项目摘要：失调的程序性细胞死亡导致重大健康问题：死亡太少导致癌症和 自身免疫和过多的死亡导致骨髓疾病，如骨髓增生异常综合征(MDS)和阿尔茨海默氏症 疾病。MDS的主要健康问题源于关键细胞的死亡，导致心脏应激和感染。在……里面 为了在关键的造血祖细胞、造血干细胞丧失的情况下维持造血功能 必须主动循环，使它们暴露在突变之下，并可能推动MDS向急性 髓系白血病(AML)。了解细胞死亡调控的机制将有助于对疾病的重要认识 发病机制和向恶性肿瘤的转化，以及治疗干预的新靶点。 有两个主要的调控途径用于诱导细胞死亡：凋亡和坏死。而基因途径和 导致细胞凋亡的机制已经得到了广泛的研究，但对那些导致坏死的机制了解较少。 此外，引发炎症反应的是坏死，而不是细胞凋亡。坏死有助于病原体清除 感染，但在中风和心肌梗死等急性损伤中会造成额外的组织损伤。 死亡受体的激活可以诱导细胞的凋亡性和坏死性死亡。令人兴奋的最新数据表明，组件 上游的凋亡信号通路，包括Caspase 8和Flip，抑制坏死，提示存在 早期的信号转换决定了细胞的命运。多条证据表明Bid是上游死亡的一个组成部分 受体-信号通路。我们已经开发了一种小鼠模型，在该模型中，BID的丢失会导致骨髓不受限制 坏死和骨髓衰竭。此外，我们还证明RIP1激酶在原发性肝癌中升高，而BID降低 MDS样本。RIP1水平在MDS的RCMD亚型中最高。根据我们的初步发现，中心假说 这一提议的核心是，只有BH3的Bid在造血稳态中发挥关键作用，通过抑制坏死，可能通过 通过Caspase 8(外源性细胞凋亡)和Rip Kinase(坏死)接收和执行肿瘤坏死因子下游的信号。 中心假设，我们建议通过定义Bid与Bid的相互作用来剖析Bid抑制坏死(SA1)的机制 促坏死性信号复合体。我们将通过Rip激酶进一步确定Bid对细胞死亡信号的影响。开始，开始 探讨异常的坏死信号对骨髓功能的影响(SA2)，我们将剖析Bid-2的作用。 造血干/祖细胞增殖、分化和再生过程中的细胞凋亡和坏死 显示无节制的骨髓坏死的小鼠模型。(SA3)将研究原发人类MDS的坏死信号 骨髓样本与MDS各亚型的坏死率和转归的相关性。我们将进一步评估 MDS样本中坏死抑制物预防骨髓细胞死亡的能力。

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.