PPAR-delta as a Novel Therapeutic Target in Asthma

项目总结 哮喘影响着3亿人，发病率和医疗费用都很高。需要改进的治疗方法， 因为目前的治疗方法有副作用，对许多患者无效。哮喘 病理生理学涉及许多不同细胞类型的复杂调节机制，目前仍知之甚少 很多层次。这项研究将测试一种新的哮喘调节靶点--孤儿核激素的作用 受体过氧化物酶体增殖物激活受体δ(PPARδ)。根据初步发现，PPARδ起作用 在肺内调节哮喘的严重程度，我们将确定其调节失调是否有助于哮喘，测试 其治疗靶向的可行性，并阐明其关键机制。呼吸道上皮细胞(AECs) 作为哮喘相关炎症的媒介和靶标，这一点非常重要。初步数据显示，PPARδ 在哮喘患者的AEC和过敏性呼吸道疾病(AAD)小鼠的肺组织中表达下调，并且 在全球范围内，下调PPARδ会加重AAD，而增加PPARδ活性则会缓解这种情况。我们的整体 目的是阐明PPARδ在调节哮喘严重程度中的作用及其机制。目标 1)确定哮喘诱导PPARδ泛素化和降解的潜在机制- 相关细胞因子以及由此导致的PPARδ缺陷是否加剧了AAD的发病和严重程度。 野生型AAD小鼠与具有全局或AEC特异性的新品系小鼠反应的比较 PPARδ缺乏症；2)测试新型PPARδ激动剂治疗是否阻断哮喘相关效应 细胞因子和激动剂诱导的或结构性的PPARδ激活通过特异性途径改善哮喘严重程度 AECS。这些研究将开发我们的新资源，包括PPARδKO小鼠，它们的胎儿死亡率低于 阻碍了先前的研究，一种新的小鼠品系表达具有结构性活性的PPARδ，特异性地在 我们开发的AECs和PPARδ激动剂，特别适合吸入给药，首选 哮喘治疗。综上所述，我们的结果将极大地促进对PPARδ在肺中作用的理解 生物学和疾病，并确定改进哮喘治疗的新靶点。

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.