Role of PPARy in Lymphocyte Survival and Transformation

PPARy 在淋巴细胞存活和转化中的作用

基本信息

批准号：
7037498
负责人：
Y. Lynn Wang
金额：
$ 13.07万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7037498
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

项目摘要

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）：该研究建议的长期目标是调查如何代谢调节剂会影响淋巴细胞存活。调节细胞存活对于维持造血系统的体内平衡很重要细胞失败死亡在慢性白血病的发病机理中起作用和懒惰的淋巴瘤。最近对汤普森博士实验室的调查已经证明了上游代谢途径的扰动线粒体电子传输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，通过提高高效来维持线粒体稳态在底物条件下，ADP耦合的氧化磷酸化局限性。鉴于这些发现，我们假设影响影响的因素细胞代谢活性可能会对细胞存活产生影响。过氧化物酶体已经选择了增生剂激活的受体伽马（Ppargamma）来测试我们假设由于其在代谢调节中的作用。 ppargamma是一个核激素受体/转录因子。在配体约束时，它激活参与脂肪酸和甘油三酸酯合成中的靶基因脂肪组织。最近的研究表明，ppargamma也在 T淋巴细胞可能在免疫调节中起作用。我们有证明用15d-pgj2和 CIGLITAZONE，PPARY的配体，有选择地诱导B和T细胞的死亡。此外，我们已经证明了ppargamma配体诱导的淋巴细胞死亡 BCI-XL不能阻止。这些发现表明ppargamma配体是潜在可用于治疗过表达Bcl-2的淋巴瘤，此类作为卵泡淋巴瘤。我们试图确定分子和代谢 pparygamma配体诱导死亡的机制。这个特定的目的提案是：1）确定L5D-PGJ2诱导的死亡和 Ciglitazone使用已建立的造血细胞通过ppargamma介导线和原发性淋巴细胞； 2）确定ppargamma的影响关于已知凋亡和生存途径的配体以及细胞代谢； 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。了解机制调节丘疹细胞的代谢可能会导致发展血液学疾病的新型治疗策略。