Role of PPARy in Lymphocyte Survival and Transformation

描述(由申请人提供)： 这项研究提案的长期目标是调查如何 代谢调节剂影响淋巴细胞存活。细胞存活的调控 对维持血液系统的动态平衡很重要 细胞死亡失败在慢性白血病发病机制中的作用 和惰性淋巴瘤。汤普森博士实验室的最新研究 已经证明了新陈代谢途径上游的扰动 线粒体电子传递导致线粒体完整性丧失， 细胞色素c的释放和细胞死亡。BCI-XL，一种抗细胞凋亡蛋白 BCL-2家族，通过促进高效率维持线粒体动态平衡 底物条件下ADP偶联氧化磷酸化 限制。根据这些发现，我们假设影响因素 细胞代谢活动可能对细胞存活有影响。过氧酶体 已选择增殖物激活受体伽马(PPARGamma)来测试我们的 假说，因为它在新陈代谢调节中的作用。PPARGamma是一种 核激素受体/转录因子。在配体结合时，它 激活与脂肪酸和甘油三酯合成有关的靶基因 脂肪组织。最近的研究表明，PPARGamma也在 T淋巴细胞，并可能在免疫调节中发挥作用。我们有 证明15d-PGJ2和15d-PGJ2对小鼠淋巴细胞的作用 环格列酮是PPARy的配体，选择性地诱导B和T细胞死亡。 此外，我们还证明了PPARγ配体诱导的淋巴细胞死亡 BCI-XL不能预防。这些发现表明，PPARGamma配体是 对治疗过表达Bcl-2的淋巴瘤有潜在的帮助，如 为滤泡性淋巴瘤。我们试图确定分子和新陈代谢 PPARyGamma配体诱导死亡的机制。这样做的具体目的是 建议：1)确定15d-PGJ2诱导的死亡和 利用已建立的造血细胞通过PPAR-γ介导西格列酮 细胞和原代淋巴细胞；2)确定PPARγ的作用 已知的凋亡和生存途径上的配体，以及细胞代谢；3) 识别PPAR-γ激活在造血细胞中诱导的基因 利用基因表达微阵列技术。了解相关机制 调节造血细胞的新陈代谢可能会导致 血液病治疗新策略的发展。

DESCRIPTION (provided by applicant): The long-term objective of this research proposal is to investigate how metabolic regulators affect lymphocyte survival. Regulation of cell survival is important in maintaining the homeostasis of the hematopoietic system and failure of cells to die plays a role in the pathogenesis of chronic leukemias and indolent lymphomas. Recent investigations in Dr. Thompson's laboratory have demonstrated that perturbation in metabolic pathways upstream of mitochondrial electron transport leads to loss of mitochondria integrity, cytochrome c release and cell death. BCI-XL, an antiapoptotic protein of the Bcl-2 family, maintains mitochondrial homeostasis by promoting efficient ADP-coupled oxidative phosphorylation under conditions of substrate limitation. In light of these findings, we hypothesize that factors affecting cellular metabolic activities may have impacts on cell survival. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been chosen to test our hypothesis because of its role in metabolic regulation. PPARgamma is a nuclear hormone receptor/transcriptional factor. Upon ligand binding, it activates target genes involved in fatty acid and triglyceride synthesis in adipose tissue. Recent studies have shown that PPARgamma is also expressed in T lymphocytes and it may play a role in immunomodulation. We have demonstrated that treatment of murine lymphocytes with 15d-PGJ2 and ciglitazone, ligands of PPARy, selectively induce death of B and T cells. Furthermore, we have shown that the PPARgamma ligand-induced lymphocyte death is not prevented by BCI-XL. These findings suggest that PPARgamma ligands are potentially useful for the treatment of lymphomas overexpressing Bcl-2, such as follicular lymphomas. We seek to determine the molecular and metabolic mechanisms of PPARygamma ligand-induced death. The specific aims of this proposal are: 1) To determine whether death induced by l5d-PGJ2 and ciglitazone is mediated through PPARgamma using established hematopoietic cell lines and primary lymphocytes; 2) To determine the effects of PPARgamma ligands on known apoptotic and survival pathways, and cellular metabolism; 3) Identify genes that are induced by PPARgamma activation in hematopoietic cells using gene expression microarray technology. Understanding the mechanisms that regulate the metabolism of hernatopoietic cells may lead to the development of novel therapeutic strategies for hematologic disorders.