Necrosis regulation of bone marrow function

项目概要：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， 自身免疫，过多的死亡会导致骨髓疾病，如骨髓增生异常综合征（MDS）和阿尔茨海默氏症 疾病MDS的主要健康问题来自于导致心脏应激和感染的关键细胞的死亡。在 为了维持造血功能，面对造血祖细胞的丧失，造血干细胞 必须积极循环，使它们暴露于诱变，并可能推动MDS转化为急性白血病的高速率 骨髓性白血病（AML）。了解细胞死亡调节机制将导致对疾病的重要见解 发病机制和恶性转化，以及治疗干预的新靶点。 有两种主要的调节途径用于诱导细胞死亡：凋亡和坏死。虽然基因通路和 驱动凋亡性细胞死亡的机制已被广泛研究，驱动坏死的机制尚不清楚。 此外，坏死而不是凋亡触发炎症反应。坏死促进病原体清除， 感染，但在急性损伤如中风和心肌梗塞中引起额外的组织损伤。 死亡受体激活可诱导凋亡和坏死细胞死亡。令人兴奋的最新数据表明， 上游凋亡信号通路，包括Caspase 8和FLIP，抑制坏死，表明存在一种抑制细胞凋亡的机制。 决定细胞命运的早期信号开关。多条证据线placeBid作为上游死亡的组成部分 受体信号通路我们已经建立了一个小鼠模型，其中Bid的丢失导致骨髓不受限制 坏死和骨髓衰竭。此外，我们证明，Rip 1激酶升高，Bid降低，在原发性肝癌中， MDS样品。Rip 1水平在MDS的RCMD亚型中最高。根据我们的初步发现，中心假设 这一建议的一个重要原因是，BH 3-only Bid通过抑制坏死，可能通过 通过Caspase 8（外源性凋亡）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Bid与SA 1的相互作用来剖析Bid抑制坏死（SA 1）的机制。 促坏死信号复合物我们将通过Rip激酶进一步确定Bid对细胞死亡信号的影响。开始 研究失调的坏死信号对骨髓功能的影响（SA 2），我们将剖析Bid-1的作用。 介导的凋亡和坏死对造血干细胞和祖细胞增殖、分化和再生的影响 显示无限制骨髓坏死的小鼠模型。(SA3)将研究原发性人类MDS中的坏死信号传导 骨髓样本，以关联MDS亚型中坏死的活化和结果。我们将进一步评估 坏死抑制剂防止MDS样品中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.