Role of PPARy in Lymphocyte Survival and Transformation

描述（由申请人提供）： 这项研究计划的长期目标是研究如何 代谢调节剂影响淋巴细胞存活。 细胞存活的调节 在维持造血系统的稳态中是重要的， 细胞不能死亡在慢性白血病的发病机制中起作用 和惰性淋巴瘤。 汤普森博士实验室最近的研究 已经证明，扰动上游的代谢途径， 线粒体电子传递导致线粒体完整性的丧失， 细胞色素C释放和细胞死亡。 BCI-XL，一种抗凋亡蛋白， Bcl-2家族，通过促进高效率的细胞凋亡来维持线粒体的稳态， 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， 细胞代谢活动可能影响细胞存活。 过氧化物酶 选择增殖物激活受体γ（PPARgamma）来测试我们的 因为它在代谢调节中的作用。 PPARgamma是一种 核激素受体/转录因子。 在配体结合时， 激活参与脂肪酸和甘油三酯合成的靶基因， 脂肪组织 最近的研究表明，PPARgamma也表达于 T淋巴细胞，它可能发挥免疫调节作用。 我们有 证明用15 d-PGJ 2和15 d-PGJ 2处理小鼠淋巴细胞， 环格列酮（ciglitazone），PPAR γ的配体，选择性地诱导B和T细胞的死亡。 此外，我们已经表明，PPARgamma配体诱导的淋巴细胞死亡， BCI-XL无法阻止。 这些发现表明，PPARgamma配体是 可能用于治疗过表达Bcl-2的淋巴瘤， 滤泡性淋巴瘤 我们试图确定分子和代谢 PPARy γ配体诱导死亡的机制。 具体目标是 建议：1）确定15 d-PGJ_2诱导的死亡和 使用已建立的造血细胞通过PPAR γ介导环格列酮 细胞和原代淋巴细胞; 2）确定PPARgamma 已知凋亡和存活途径的配体，以及细胞代谢; 3） 鉴定造血细胞中由PPARgamma激活诱导的基因 使用基因表达微阵列技术。 了解机制 调节造血细胞代谢的机制可能导致 开发血液病的新治疗策略。

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.