TGFb Modulation: Therapeutic Targeting for COPD-Emphysema

描述(申请人提供)：COPD是一种复杂的肺部疾病，具有明显的间隔性表现，挑战单基因或单途径因果关系的简单概念。然而，上皮下纤维化和成纤维细胞增殖的呼吸道表现似乎反映了丰富的基质沉积，而间隔丢失和细胞凋亡的空隙表现相反地提示基质缺乏或吸收。一条可以对抗基质紊乱、炎症和降低细胞存活率的途径是TGFb级联反应。TGFb家族的生长因子在组织内稳态、细胞存活和分化中发挥重要作用。我们提供的最新数据表明，血管紧张素受体拮抗剂拮抗TGFb可以改善CS诱导的动物模型的肺损伤。目前的建议旨在确定TGFb途径是否为COPD的可行治疗靶点，并开发能够合理靶向该途径的药物。在目标1中，我们将TGFb信号间隔缺陷的遗传靶向动物模型应用于慢性香烟烟雾暴露，以确定在CS诱导的小鼠肺气肿中TGFb调节失调的主要部位。在目标2中，我们将在已建立的CS诱导的肺气肿动物模型中测试一种TGFb信号的小分子拮抗剂，该小分子拮抗剂可以特异性地抑制I型TGFbeta受体(ALK5)的临床前疗效。作为原理的证明，我们还将合成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，以实现最佳的肺远端递送。最后，在目标3中，利用临床验证的方法，我们从两组患者中确定了系统和/或肺特异性TGFb1水平是否是COPD患者药理疗效的生物标记物：COPD患者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，LTRC提供的样本来自不同严重程度的COPD患者。完成后，这些研究将1)确定COPD中TGFb信号异常的区隔方面，2)验证和探索新的抗TGFb疗法作为治疗该疾病的合理方法，以及3)确定血清或肺组织中TGFb配体的水平是否可以用作针对这一途径的临床研究的药理学生物标志物。相关性(见说明)；慢性阻塞性肺病很常见，费用昂贵，临床负担沉重。尽管它是美国第四大致死原因，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。在目前的方案中，我们利用人类材料、动物模型系统和候选治疗药物，对TGFb通路作为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.