TGFb Modulation: Therapeutic Targeting for COPD-Emphysema

描述（由申请人提供）：COPD是一种复杂的肺部疾病，具有明显的室间性表现，挑战单一基因或单一途径因果关系的简单概念。虽然气道上皮下纤维化和成纤维细胞增殖的表现似乎反映了旺盛的基质沉积，但气道中隔缺失和细胞凋亡的表现则相反，表明基质缺乏或吸收。介导基质紊乱、炎症和细胞存活降低的途径之一是TGFb级联。TGFb家族生长因子在组织稳态、细胞存活和分化中起着至关重要的作用。我们提供的最新数据显示，TGFb拮抗剂与血管紧张素受体阻断剂可以改善动物模型中cs诱导的肺损伤。目前的提案旨在确定TGFb途径是否是COPD的可行治疗靶点，并开发能够合理靶向该途径的药物。在Aim 1中，我们将TGFb信号区隔缺陷的遗传靶向动物模型置于慢性香烟烟雾暴露中，以确定小鼠cs诱导的肺气肿中TGFb失调的主要部位。在Aim 2中，我们将在已建立的CS诱导肺气肿动物模型中测试TGFb信号的小分子拮抗剂，该拮抗剂特异性抑制I型tgf β受体（Alk5）的临床前疗效。作为原理证明，我们还将合成一种血管紧张素受体阻滞剂的纳米颗粒配方，我们发现这类药物通过抑制TGFb来改善cs暴露小鼠的肺组织学，以实现最佳的远端肺输送。最后，在Aim 3中，利用临床验证的方法，我们从两组患者中确定全身和/或肺特异性TGFbl水平是否是COPD患者药理学疗效的生物标志物：一组是在试点临床试验中接受血管紧张素受体阻滞剂氯沙坦治疗的COPD患者，另一组是由LTRC不同严重程度COPD患者标本库提供的标本。完成后，这些研究将1)确定COPD中TGFb信号失调的区室方面，2)验证和探索新的抗TGFb疗法作为该疾病的合理方法，3)确定TGFb配体的血清或肺水平是否可以用作针对该途径的临床研究的药理学生物标志物。相关性（见说明书）；慢性阻塞性肺病是一种常见、昂贵且临床负担沉重的疾病。虽然它是美国第四大死亡原因，但没有任何治疗方法可以改变这种高度病态疾病的自然历史。在目前的提案中，我们利用人体材料、动物模型系统和候选治疗剂，对TGFb途径作为COPD治疗的合理靶点进行了详细的评估。

DESCRIPTION (provided by applicant): COPD is a complex lung disorder with distinct compartmental manifestations which challenge simplistic notions of single gene or single pathway causality. Whereas the airway findings of subepithelial fibrosis and fibroblast proliferation seem to reflect exuberant matrix deposition, the airspace findings of septal loss and cellular apoptosis conversely suggest matrix deficiency or resorption. One pathway that can negotiate matrix disturbances, inflammation and reduced cell survival is the TGFb cascade. The TGFb family of growth factors plays critical roles in tissue homeostasis, cell survival and differentiation. We present recent data showing that TGFb antagonism with angiotensin receptor blockade ameliorates CS-induced lung injury in animal models. The current proposal seeks to determine whether TGFb pathway is a viable therapeutic target for COPD and develop agents which can rationally target this pathway. In Aim 1, we subject genetically targeted animal models harboring compartmental deficiencies in TGFb signaling to chronic cigarette smoke exposure to determine the primary site of TGFb dysregulation in murine CS-induced emphysema. In Aim 2, we will test a small molecule antagonist of TGFb signaling that specifically inhibits the type I TGFbeta receptor (Alk5) for preclinical efficacy in an established animal model of CS induced emphysema. As proof of principle, we will also synthesize a nanoparticle formulation of an angiotensin receptor blocker, a class of agents that we have found improves lung histology in CS-exposed mice via TGFb inhibition, for optimal distal lung delivery. Finally, in Aim 3, utilizing a clinically validated methodology, we determine whether systemic and/or lung specific TGFbl levels are biomarkers of pharmacologic efficacy in COPD pts from two cohorts of patients: COPD patients being treated with Losartan, an angiotensin receptor blocker, in a pilot clinical trial and specimens provided by the LTRC repository of specimens from patients with COPD of varying severity. Upon completion, these studies will 1) identify the compartmental aspects of dysregulated TGFb signaling in COPD, 2) validate and explore novel antiTGFb therapies as rational approaches for the disorder and 3) establish whether serum or lung levels of TGFb ligands can be used as a pharmacologic biomarkers for clinical studies targeting this pathway. RELEVANCE (See instructions); COPD is common, costly and clinically burdensome. Although it is the fourth leading cause of death in the United States, there are no treatments that alter the natural history of this highly morbid disorder. In the current proposal, we perform a detailed evaluation of the TGFb pathway as a rational target for COPD treatment utilizing human materials, animal model systems and candidate therapeutic agents.