PPAR-delta as a Novel Therapeutic Target in Asthma

PPAR-δ 作为哮喘的新治疗靶点

• 批准号: 9282803
• 负责人: RAJU C REDDY
• 金额: $ 50.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282803
• 关键词: Adverse effects; Affect; Agonist; Allergens; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Asthma; Automobile Driving; Binding; Biology; Breathing; Cells; Clinical; Collaborations; Complex; Consensus; Data; Development; Dictyoptera; Disease; Down-Regulation; Epithelial Cells; F-Box Proteins; Failure; Feedback; Fetal Mortality Statistics; Functional disorder; Genetic; Goals; Health Care Costs; Heterogeneity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhalation Drug Administration; Knock-out; Knockout Mice; Lung; Lung diseases; Mediating; Mediator of activation protein; Molecular; Molecular Biology; Morbidity - disease rate; Mouse Strains; Mus; Nuclear Hormone Receptors; Orphan; Ovalbumin; PPAR delta; Pathogenesis; Patient-Focused Outcomes; Patients; Peroxisome Proliferator-Activated Receptors; Phosphotransferases; Preparation; Prevalence; Receptor Cell; Research; Resources; Role; Series; Severities; Severity of illness; Signal Pathway; Specificity; Testing; Therapeutic; Ubiquitination; Validation; Water; allergic airway disease; asthmatic patient; base; cell type; cytokine; experience; improved; in vivo; knock-down; mouse model; new therapeutic target; novel; novel therapeutics; prevent; receptor; response; therapeutic target; tool; transcription factor; ubiquitin-protein ligase

PROJECT SUMMARY Asthma affects >300 million people, with high morbidity and healthcare costs. Improved therapies are needed, because current therapies have adverse side effects and are ineffective in many patients. Asthma pathophysiology involves complex regulatory mechanisms in many different cell types, still little-understood at many levels. This research will test the role of a novel regulatory target in asthma, the orphan nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ). Based on preliminary findings that PPARδ acts within the lung to modulate asthma severity, we will determine if its dysregulation contributes to asthma, test feasibility of its therapeutic targeting, and elucidate key mechanisms. Airway epithelial cells (AECs) are important as both mediators and targets of asthma-related inflammation. Preliminary data suggest that PPARδ is downregulated in AECs of asthma patients and lungs of mice with allergic airway disease (AAD), and that globally downregulating PPARδ exacerbates AAD, whereas increasing PPARδ activity alleviates it. Our overall goal is to elucidate the role of PPARδ in regulating asthma severity and the mechanisms involved. The aims are: 1) to determine the mechanisms underlying induction of PPARδ ubiquitination and degradation by asthma- related cytokines and whether the resulting PPARδ deficiency exacerbates AAD pathogenesis and severity, comparing responses of wild-type AAD-bearing mice with those of novel strains having global or AEC-specific PPARδ deficiency; 2) to test whether treatment with novel PPARδ agonists blocks effects of asthma-related cytokines and agonist-induced or constitutive PPARδ activation ameliorates asthma severity specifically via AECs. These studies will exploit our novel resources including PPARδ KO mice lacking the fetal mortality that has hampered previous studies, a novel mouse strain expressing constitutively active PPARδ specifically in AECs, and PPARδ agonists we developed that are uniquely suited to administration by inhalation, preferred for asthma treatment. Taken together, our results will significantly advance understanding of PPARδ roles in lung biology and disease, and identify a new target for improved asthma therapy.

项目摘要 哮喘影响> 3亿人，发病率高和医疗保健费用。需要改进的疗法， 因为当前的疗法具有不良的副作用，并且在许多患者中无效。哮喘 病理生理学涉及许多不同细胞类型中的复杂调节机制，但仍未理解 许多级别。这项研究将测试新型调节目标在哮喘中的作用 受体过氧化物增殖物激活的受体δ（PPARδ）。基于初步发现PPARδ起作用 在肺部调节哮喘严重程度内，我们将确定其功能障碍是否有助于哮喘，测试 其治疗靶向的可行性并阐明了关键机制。气道上皮细胞（AEC）是 与哮喘相关炎症的介体和靶标重要。初步数据表明PPARδ 在患有过敏性气道疾病（AAD）的哮喘患者和肺的AEC中被下调， 全球下调PPARδ加剧了AAD，而PPARδ活性的增加会减轻它。我们的整体 目标是阐明PPARδ在确定哮喘严重程度和所涉及的机制中的作用。目的 为：1）确定哮喘 - 胰腺泛素化和降解的基础机制 相关的细胞因子以及所得的PPARδ缺乏是否加剧AAD发病机理和严重程度， 比较野生型AAD小鼠的反应与具有全球或AEC特异性菌株的新型菌株的反应 PPARδ缺乏； 2）测试使用新型PPARδ激动剂治疗是否阻止哮喘相关的影响 细胞因子和激动剂诱导的或组成型PPARδ激活可通过专门通过 AEC。这些研究将利用我们的新资源，包括缺乏胎儿死亡率的PPARδKO小鼠 已经妨碍了先前的研究，一种新型的小鼠菌株在 我们开发的AEC和​​PPARδ激动剂非常适合通过吸入，首选 哮喘治疗。综上所述，我们的结果将显着提高对肺中PPARδ作用的理解 生物学和疾病，并确定改善哮喘治疗的新靶标。