Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
基本信息
- 批准号:8490706
- 负责人:
- 金额:$ 56.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-15 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adrenal Cortex HormonesAgingAgonistAllyAnimal ModelAnti-CholinergicsAntioxidantsApoptoticBiological MarkersBreathingCell AgingCellsChemopreventive AgentChronicChronic BronchitisChronic Obstructive Airway DiseaseClinical TrialsDataDevelopmentDiseaseDisease ProgressionDysplasiaEnvironmental Risk FactorEtiologyExtracellular MatrixFDA approvedFailureFundingGenotoxic StressGoalsHumanIloprostImageIndividualInflammationInflammatoryInterventionIntraepithelial NeoplasiaInvestigationLeadLigandsLinkLungLung InflammationLung NeoplasmsLung diseasesMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMediator of activation proteinModelingModificationMolecularMusObstructionOrganOxidantsOxidative StressPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhase II Clinical TrialsPioglitazonePositioning AttributePremalignantProcessProstaglandins IProteolysisPulmonary EmphysemaResearchRetinoidsRiskSafetySignal TransductionSmokeSmokerStructure of parenchyma of lungSupplementationTestingTobaccoTobacco smokeVitaminsanalogbasecancer chemopreventioncancer riskdisease phenotypehigh riskinsightlung carcinogenesislung injuryneoplasticnovelpreclinical studyresearch study
项目摘要
DESCRIPTION (provided by applicant): Smokers with the overlapping COPD phenotypes of airflow obstruction, chronic bronchitis or emphysema carry a significantly higher risk of developing lung cancer, as two recent studies indicated that emphysema detected by CT imaging may be a stronger predictor of lung cancer risk than spirometric airflow obstruction. Lung inflammation and excessive extracellular matrix proteolysis have been implicated as mediators of lung injury by tobacco smoke. Furthermore, tobacco smoke-triggered oxidative stress initiates lung inflammation and progressively disrupts cellular signaling involved in maintenance of lung integrity, eventually leading to organ aging and cell senescence. There are as yet no specific treatments for tobacco smoke-induced lung diseases that target the reversal of lung tissue destruction and promote differentiation for protecting lung tissue. Our goal is to develop novel treatments that target COPD progression and lung cancer simultaneously, based on mechanistic studies of molecular pathways that protect lung tissue from the pathogenesis of both tobacco-smoke induced diseases. Our preclinical studies have documented that prostacyclin supplementation protects against tobacco smoke-induced lung diseases, including COPD and the pre-neoplastic changes observed prior to lung cancer. We hypothesize that activation of the prostacyclin - PPAR3 axis with prostacyclin analogues and PPAR3 agonists has cytoprotective effects in tobacco smoke-induced lung disease, leading to concomitant protection from lung destruction in patients with COPD and development of the transition of epithelial dysplasia to cancer. In specific aim 1, we will determine whether PPAR3 signaling enhancement has a pro-differentiation, chemopreventive effect in individuals at risk for lung cancer and decreases lung inflammation in COPD patients. In specific aim 2, we will pursue inflammation biomarkers that characterize responders versus non-responders to PPAR3 modifying therapies. In specific aim 3, we will demonstrate in murine models that PPAR3 signaling enhancing therapies (iloprost or pioglitazone) can diminish tobacco smoke-induced lung injury; thereby decreasing the occurrence of tobacco smoke-induced lung tumors. Because the drugs being studied are already FDA approved with established safety profiles, our research could yield new treatments relatively soon that target the reversal of lung tissue destruction and promote lung tissue protection for the tobacco smoke-induced lung diseases COPD and lung cancer.
描述(由申请人提供):具有气流阻塞、慢性支气管炎或肺气肿的重叠COPD表型的吸烟者发生肺癌的风险显著更高,因为最近的两项研究表明,通过CT成像检测到的肺气肿可能是比肺量测定气流阻塞更强的肺癌风险预测因子。肺炎症和过度的细胞外基质蛋白水解被认为是烟草烟雾引起的肺损伤的介质。此外,烟草烟雾引发的氧化应激引发肺部炎症并逐渐破坏参与维持肺完整性的细胞信号传导,最终导致器官老化和细胞衰老。目前还没有针对烟草烟雾诱导的肺部疾病的特异性治疗方法,其靶向逆转肺组织破坏并促进分化以保护肺组织。我们的目标是开发同时针对COPD进展和肺癌的新型治疗方法,基于对保护肺组织免受烟草烟雾诱导的疾病发病机制影响的分子途径的机制研究。我们的临床前研究已经证明,前列环素补充剂可以预防烟草烟雾引起的肺部疾病,包括COPD和肺癌前观察到的肿瘤前变化。我们假设前列环素类似物和PPAR 3激动剂激活前列环素-PPAR 3轴在烟草烟雾诱导的肺病中具有细胞保护作用,导致COPD患者的肺破坏和上皮异型增生向癌症转变的发展的伴随保护。在具体目标1中,我们将确定PPAR 3信号传导增强是否在处于肺癌风险的个体中具有促分化、化学预防作用,并减少COPD患者的肺部炎症。在具体目标2中,我们将追求表征对PPAR 3修饰疗法的应答者与非应答者的炎症生物标志物。在具体目标3中,我们将在鼠模型中证明PPAR 3信号传导增强疗法(伊洛前列素或吡格列酮)可以减少烟草烟雾诱导的肺损伤;从而减少烟草烟雾诱导的肺肿瘤的发生。由于正在研究的药物已经获得FDA批准,并具有既定的安全性,因此我们的研究可能会在相对较短的时间内产生新的治疗方法,这些方法可以逆转肺组织的破坏,并促进肺组织对烟草烟雾引起的肺部疾病COPD和肺癌的保护。
项目成果
期刊论文数量(0)
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{{ truncateString('MARK W GERACI', 18)}}的其他基金
Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
- 批准号:
8320228 - 财政年份:2011
- 资助金额:
$ 56.42万 - 项目类别:
Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer
COPD 和肺癌中前列环素-PPARy 轴的共同靶向
- 批准号:
8097154 - 财政年份:2011
- 资助金额:
$ 56.42万 - 项目类别:
53rd Annual Thomas L Petty Aspen Lung Conference: Systems Biology of Lung Disease
第 53 届 Thomas L Petty Aspen 肺病年度会议:肺部疾病的系统生物学
- 批准号:
8005685 - 财政年份:2010
- 资助金额:
$ 56.42万 - 项目类别:
Prostacyclin Synthase and Receptors in Pulmonary Arterial Hypertension
肺动脉高压中的前列环素合酶和受体
- 批准号:
7824361 - 财政年份:2009
- 资助金额:
$ 56.42万 - 项目类别:
Molecular Physiology Core Applied to Acute Lung Injury
分子生理学核心应用于急性肺损伤
- 批准号:
7936177 - 财政年份:2009
- 资助金额:
$ 56.42万 - 项目类别:
Molecular Physiology Core Applied to Acute Lung Injury
分子生理学核心应用于急性肺损伤
- 批准号:
7859480 - 财政年份:2009
- 资助金额:
$ 56.42万 - 项目类别:
Mechanisms of Prostacyclin signaling in Pulmonary Arterial Hypertension
肺动脉高压中前列环素信号传导机制
- 批准号:
7662797 - 财政年份:2009
- 资助金额:
$ 56.42万 - 项目类别:
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