Role of PPARy in Lymphocyte Survival and Transformation

PPARy 在淋巴细胞存活和转化中的作用

• 批准号: 6422676
• 负责人: Y. Lynn Wang
• 金额: $ 13.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6422676
• 关键词: BCL2 gene /protein; apoptosis; cell death; cell growth regulation; cell line; cellular respiration; gene expression; glucose metabolism; hematopoietic stem cells; laboratory mouse; leukocyte activation /transformation; lipid metabolism; lymphatic tissue; lymphoma; microarray technology; oxidative phosphorylation; peroxisome proliferator activated receptor; tissue /cell culture

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.

描述（由申请人提供）： 本研究计划的长期目标是研究如何 代谢调节因子影响淋巴细胞的存活。 细胞存活的调节 对于维持造血系统的稳态很重要 细胞死亡失败在慢性白血病的发病机制中发挥作用 和惰性淋巴瘤。 汤普森博士实验室的最新调查 已经证明，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释放和细胞死亡。 BCI-XL，一种抗凋亡蛋白 Bcl-2 家族，通过促进有效的线粒体维持稳态 底物条件下 ADP 偶联的氧化磷酸化 局限性。 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产生影响。 过氧化物酶体 选择增殖物激活受体γ（PPARγ）来测试我们的 假设是因为它在代谢调节中的作用。 PPARγ 是一种 核激素受体/转录因子。 配体结合后，它 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淋巴细胞可能在免疫调节中发挥作用。 我们有 证明用 15d-PGJ2 和 ciglitazone 是 PPARy 的配体，选择性诱导 B 细胞和 T 细胞死亡。 此外，我们还发现 PPARgamma 配体诱导的淋巴细胞死亡 BCI-XL 不会阻止。 这些发现表明 PPARgamma 配体 可能有助于治疗过度表达 Bcl-2 的淋巴瘤，例如 如滤泡性淋巴瘤。 我们寻求确定分子和代谢 PPARγγ配体诱导死亡的机制。 本次活动的具体目标 建议是： 1) 确定是否由l5d-PGJ2和 环格列酮通过 PPARgamma 使用已建立的造血细胞介导 细胞系和原代淋巴细胞； 2) 确定PPARgamma的作用 已知的细胞凋亡和生存途径以及细胞代谢的配体； 3） 鉴定造血细胞中 PPARgamma 激活诱导的基因 使用基因表达微阵列技术。 了解机制 调节造血细胞的代谢可能导致 开发血液疾病的新治疗策略。