TGFb Modulation: Therapeutic Targeting for COPD-Emphysema

TGFb 调节：COPD 肺气肿的治疗靶向

• 批准号: 8073728
• 负责人: Enid R Neptune
• 金额: $ 49.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073728
• 关键词: Angiotensin Receptor; Animal Model; Apoptosis; Biological Markers; Biological Models; Cause of Death; Cell Differentiation process; Cell Survival; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Clinical Trials; Complex; Data; Deposition; Disease; Distal; Drug Formulations; Etiology; Evaluation; Exposure to; Family; Fibroblasts; Fibrosis; Genes; Growth Factor; Histology; Homeostasis; Human; Inflammation; Instruction; Ligands; Losartan; Lung; Lung diseases; Mediation; Methodology; Mus; Natural History; Pathway interactions; Patients; Play; Pulmonary Emphysema; Role; Serum; Severities; Signal Transduction; Site; Specimen; Testing; Therapeutic Agents; Tissues; Transforming Growth Factor beta; United States; cigarette smoking; cohort; improved; lung injury; nanoparticle; novel; preclinical efficacy; receptor; repository; small molecule; therapeutic target

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.

描述（由申请人提供）：COPD是一种复杂的肺疾病，具有独特的隔室表现，挑战了单基因或单一途径因果关系的简单概念。尽管上皮下纤维化和成纤维细胞增殖的气道发现似乎反映了旺盛的基质沉积，但相反，空体损失和细胞凋亡的空域发现表明基质缺乏或吸收。可以协商基质干扰，炎症和细胞存活减少的一种途径是TGFB级联。 TGFB系列生长因子家族在组织稳态，细胞存活和分化中起关键作用。我们提供了最新数据，表明与血管紧张素受体阻滞作用的TGFB拮抗作用可改善动物模型中CS诱导的肺损伤。当前的建议旨在确定TGFB途径是否是COPD的可行治疗靶标，并开发可以合理地针对该途径的剂。在AIM 1中，我们对遗传靶向的动物模型对TGFB信号传导的遗传靶向动物模型进行慢性香烟烟雾暴露，以确定鼠CS诱导的肺气肿中TGFB失调的主要部位。在AIM 2中，我们将测试TGFB信号传导的小分子拮抗剂，该拮抗剂专门抑制I型TGFBETA受体（ALK5）在CS诱导的肺气肿的已建立动物模型中的临床前疗效。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制剂，这是一种我们发现的一类药物，可以通过TGFB抑制CS暴露的小鼠中的肺组织学改善肺部组织学，以最佳的远端肺递送。最后，在AIM 3中，利用临床验证的方法学，我们确定全身和/或肺特异性TGFBL水平是否是来自两名患者的COPD PT的药理功效的生物标志物：在试验临床和coRES的患者中，在losartan，Angeotin Bocker的coPD患者中，COPD患者接受了losartan coptan的治疗。完成后，这些研究将1）确定COPD中TGFB信号失调的隔室方面，2）验证并探索新颖的抗ITGFB疗法作为疾病的合理方法，3）是否可以将血清或肺水平用于TGFB配体水平，以作为药物生物标志物作为药物生物标志物，以作为临床研究。相关性（请参阅说明）； COPD很常见，昂贵且临床上的繁重。尽管这是美国第四大死亡原因，但没有治疗方法改变这种高度病态疾病的自然史。在当前的建议中，我们对TGFB途径进行了详细评估，作为利用人类材料，动物模型系统和候选治疗剂的COPD治疗的合理目标。