PPAR-delta as a Novel Therapeutic Target in Asthma

项目摘要 哮喘影响超过3亿人，发病率高，医疗费用高。需要改进的疗法， 因为目前的疗法具有副作用并且对许多患者无效。哮喘 病理生理学涉及许多不同细胞类型的复杂调节机制， 很多层次。这项研究将测试一种新的调节靶点在哮喘中的作用，孤儿核激素 受体过氧化物酶体增殖物激活受体δ（PPARδ）。根据初步发现， 在肺内调节哮喘严重程度，我们将确定其失调是否有助于哮喘，测试 其治疗靶向的可行性，并阐明关键机制。气道上皮细胞（AEC）是 作为哮喘相关炎症的介质和靶点都很重要。初步数据表明， 在哮喘患者的AEC和过敏性气道疾病（AAD）小鼠的肺中下调， 整体下调PPARδ会加重AAD，而增加PPARδ活性则会加重AAD。 目的是阐明过氧化物酶体增殖物激活受体δ在调节哮喘严重程度中的作用及其机制。目标 目的：1）确定哮喘诱导PPARδ泛素化和降解的潜在机制- 相关的细胞因子以及由此导致的PPARδ缺乏是否会加重AAD的发病机制和严重程度， 将携带野生型AAD的小鼠的反应与具有全局或AEC特异性的新菌株的反应进行比较， PPARδ缺乏; 2）测试用新型PPARδ激动剂治疗是否阻断哮喘相关的炎症因子的作用。 细胞因子和激动剂诱导的或组成性的过氧化物酶体增殖物激活物受体δ激活可特异性地通过 AEC。这些研究将利用我们的新资源，包括没有胎儿死亡率的PPARδ KO小鼠， 阻碍了以前的研究，一种新的小鼠品系表达组成型激活的过氧化物酶体增殖物激活受体δ，特异性地在 AEC和我们开发的PPARδ激动剂，其独特地适合于通过吸入给药，优选用于 哮喘治疗综上所述，我们的研究结果将大大促进对PPARδ在肺中作用的理解， 生物学和疾病，并确定一个新的目标，改善哮喘治疗。

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.