PPAR-gamma ligands in colorectal cancer

结直肠癌中的 PPAR-γ 配体

• 批准号: 7434029
• 负责人: SEUNG Joon BAEK
• 金额: $ 19.99万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434029
• 关键词: 2,4-thiazolidinedione; Affect; Antidiabetic Drugs; Apoptosis; Apoptotic; Binding; Chemicals; Colorectal; Colorectal Cancer; Complex; Development; Environmental Risk Factor; Evolution; Family; Figs - dietary; GDF15 gene; Gene Mutation; Genes; Inflammatory Response; Ligands; Malignant Neoplasms; Metabolic Diseases; Molecular; Non-Steroidal Anti-Inflammatory Agents; Nuclear Hormone Receptors; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Play; Polyunsaturated Fatty Acids; Prevention; Prostaglandins; Protein Isoforms; RXR; Regulator Genes; Report (document); Research; Response Elements; Role; Series; Staging; Thiazolidinediones; carcinogenesis; in vivo; insight; lipid metabolism; novel; prevent; tumorigenic

DESCRIPTION (provided by applicant): The peroxisome proliferator activated receptors (PPARs) are ligand-activated nuclear hormone receptors and a potential target for the prevention and treatment of several cancers. Three isoforms have been dentified and recent evidence suggests that pharmacological activation of PPARgamma and PPARa, and inhibition of PPARgamma, may prevent cancer. PPARgamma has been extensively investigated as a target for ligands, which strongly modulate colorectal carcinogenesis. PPARgamma ligands include prostaglandins of the J series, the synthetic antidiabetic thiazolidinediones, and oxidative metabolites of polyunsaturated fatty acids. While numerous reports document the anti-tumorigenic activity of PPARgamma ligands in colorectal cancer the molecular mechanisms responsible for these effects are not known beyond PPARgamma activation. We have preliminary evidence that PPARgamma ligands induce expression of the pro-apoptotic gene NAG-1 (nonsteroidal anti-inflammatory drug activated gene) in a PPARgamma- dependent and independent manner, and hypothesize that this induction of NAG-1 plays a pivotal role in the anti-tumorigenic activity of PPARgamma ligands. The research objectives of this proposal are to understand how PPARgamma ligands regulate NAG-1 expression by different mechanisms and affect the development of colorectal cancer. This study may also provide new insights into how chemical and environmental factors influence cancer development with subsequent evolution of a new family of novel anti-tumorigenic compounds. The specific aims are; To examine the contribution of NAG-1 expression in PPARgamma ligand-induced apoptosis. To characterize cis- and trans-acting elements responsible for the induction of NAG-1 expression by PPARgamma ligands. . To examine the profile of genes which are induced by PPARgamma ligands in a PPARgamma- independent manner. IV. To investigate the in vivo anti-tumorigenic effects of a novel PPARy ligand, MCC-555, and its affects on NAG-1 expression at different stages of colorectal carcinogenesis.

描述（由申请人提供）：过氧化物酶体增殖物激活受体（PPAR）是配体激活的核激素受体，也是预防和治疗多种癌症的潜在靶标。三种同工型已被牙齿牙齿牙齿，最近的证据表明，PPARGAMMA和PPARA的药理学激活以及对Ppargamma的抑制可能会预防癌症。 Ppargamma已被广泛研究为配体的靶标，该靶标强烈调节结直肠癌的发生。 PPARGAMMA配体包括J系列的前列腺素，合成抗糖尿病硫代二酮和多不饱和脂肪酸的氧化代谢产物。虽然许多报告记录了ppargamma配体在大肠癌中的抗肿瘤活性，但负责这些作用的分子机制在ppargamma激活之外尚不清楚。我们有初步的证据表明，ppargamma配体诱导促凋亡基因Nag-1（非甾体类抗炎性药物激活的基因）的表达，依赖性且独立的方式，并假设Nag-1的这种诱导在抗thimorigenic Partivemama ligaMAMA ppargggyma ligaMa ligaMa ligaMa ligaMa ligaMa ligaMa ligaMa ligaMa ligaMa ligaMa lig lig lig lig lig lig lig lig lig lig lig lig lig lig lig ligaMa ligaMa lig ligaMa parggggyama。该提案的研究目标是了解ppargamma配体如何通过不同的机制调节NAG-1的表达并影响结直肠癌的发展。这项研究还可能提供有关化学和环境因素如何影响癌症发展的新见解，随后新型抗肿瘤化合物的新家族的演变。具体目标是；检查Nag-1表达在PPARGAMMA配体诱导的凋亡中的贡献。表征负责ppargamma配体诱导NAG-1表达的顺式和反式作用元件。 。检验以ppargamma配体诱导的基因的谱，以ppargamma-appiction方式。 iv。为了研究一种新型配体MCC-555的体内抗肿瘤效应，及其对结直肠癌不同阶段的NAG-1表达的影响。