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，具有不同的房室表现，挑战了单基因或单途径因果关系的简单概念。上皮下纤维化和成纤维细胞增殖的气道结果似乎反映了丰富的基质沉积，而隔损失和细胞凋亡的空域结果相反地表明基质缺乏或吸收。一种可以协商基质紊乱、炎症和降低的细胞存活的途径是TGF β级联。生长因子TGFb家族在组织稳态、细胞存活和分化中发挥关键作用。我们目前的最新数据表明，TGF β拮抗血管紧张素受体阻断剂改善CS诱导的肺损伤的动物模型。目前的建议旨在确定TGF β通路是否是COPD的可行治疗靶点，并开发能够合理靶向该通路的药物。在目标1中，我们将TGF β信号传导中存在房室缺陷的遗传靶向动物模型用于慢性香烟烟雾暴露，以确定小鼠CS诱导的肺气肿中TGF β失调的主要部位。在目的2中，我们将测试特异性抑制I型TGF β受体（Alk 5）的TGF β信号传导的小分子拮抗剂在CS诱导的肺气肿的已建立动物模型中的临床前功效。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制剂，我们发现这类药物通过TGF β抑制改善CS暴露小鼠的肺组织学，以实现最佳的远端肺递送。最后，在目的3中，利用临床验证的方法，我们确定全身和/或肺特异性TGF β 1水平是否是来自两组患者的COPD患者中药理学功效的生物标志物：在初步临床试验中用氯沙坦（一种血管紧张素受体阻断剂）治疗的COPD患者和由来自不同严重程度的COPD患者的标本的LTRC储存库提供的标本。完成后，这些研究将1）鉴定COPD中失调的TGF b信号传导的隔室方面，2）验证和探索新的抗TGF b疗法作为疾病的合理方法，和3）确定TGF b配体的血清或肺水平是否可以用作靶向该途径的临床研究的药理学生物标志物。相关性（见说明书）; COPD是常见病，费用高，临床负担重。虽然它是美国第四大死亡原因，但没有治疗方法可以改变这种高度病态疾病的自然史。在目前的建议中，我们进行了详细的评估TGF β通路作为合理的目标，COPD治疗利用人体材料，动物模型系统和候选治疗药物。

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.