Novel Pathways in TGF BETA Signaling

TGF BETA 信号转导的新途径

基本信息

批准号：
9336443
负责人：
Agnieszka Swiatecka-Urban
金额：
$ 35.16万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336443
关键词：
Adult Affect Alleles Binding Binding Sites Bronchiectasis Caucasians Cell physiology Cessation of life Child Chloride Channels Chronic Clinical Trials Cyclic AMP Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Disabled Persons Disease Epithelial Cells Epitopes Feeds Genes Genetic Transcription Growth Healed Health Health Care Costs Human Infection Inflammation Inflammatory Inflammatory Response Interleukins Intervention Investigation Lead Learning Lung Lung diseases Mediating Mediator of activation protein MicroRNAs Modeling Motor Movement Mutation Nuclear Nuclear Translocation Outcome Pathway interactions Patients Pharmaceutical Preparations Play Process Proteins Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Recruitment Activity Repression Respiratory Failure Respiratory physiology Role Signal Transduction Sodium Chloride T cell differentiation T-Lymphocyte Testing Therapeutic Agents Transforming Growth Factor beta Transforming Growth Factors Up-Regulation VX-770 VX-809 Water Work cell type cystic fibrosis patients cytokine healing new therapeutic target novel novel therapeutics nucleocytoplasmic transport prevent protein transport receptor response small molecule trafficking

项目摘要

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF), the most common recessive disease among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a cAMP-activated chloride ion channel. CF patients develop chronic lung infection and inflammation, which can be mediated in part by interleukin (IL)-17A leading to bronchiectasis, and ultimately respiratory failure and death. CF shares features with many other forms of lung disease where inflammation plays a major role. Ninety percent of CF patients carry at least one copy of the ∆F508 allele. Current treatment for CF lung disease is only marginally effective in CF patients with the ∆F508 mutation. A key limitation is that most CF patients produce high levels of Transforming Growth Factor (TGF)-β1. Our published work has shown that TGF-β1 represses ∆F508-CFTR transcription in HBE cells, acting upstream of the therapeutic agent VX-809 and thus blocks its efficacy. High TGF-β1 levels also prime CF patients for inflammation. Thus, TGF-β1 signaling is a major endogenous pathway limiting the efficacy of VX-809 in CF in addition to promoting inflammation. Our preliminary data confirm that VX-809 reverses neither the TGF-β1 inhibition of CFTR transcription nor the IL-17A induced secretion of inflammatory cytokines. TGF-β1 has many homeostatic effects, including would healing and T-cell differentiation. Currently it is unknown how to precisely target the pathogenic effects of TGF-β1 without compromising the homeostatic function. Targeting the cell-type specific and disease-relevant activators in the TGF-β1 pathway could serve as a novel therapeutic strategy to selectively eliminate the pathogenic sequels of TGF-β1 in CF. We have shown that Dab2 (disabled-2) may play such role acting downstream of TGF-β1 receptors, and directing nuclear trafficking of a key mediator in TGF-β1 pathway, Smad3 in human bronchial epithelial (HBE) cells. Our central hypothesis is that TGF-β1 stabilizes the Dab2-Smad3 interaction to increase nuclear delivery of Smad3 leading to repression of ∆F508-CFTR transcription and inflammation in HBE cells. Dab2 favors Smad3 signaling, blocks ∆F508-CFTR protein rescue by VX-809, feeds the pro-inflammatory cross-talk, and worsens outcomes. The Dab2-Smad3 interface thus represents a novel therapeutic target for CF and for other forms of lung disease where inflammation is mediated by TGF-β1. In aim 1, we will test the hypothesis that Dab2 and Smad3 mediate the pathogenic effects of TGF-β1 in HBE cells. In aim 2 test the hypothesis that Dab2 directs nuclear translocation of activated Smad3 specifically in HBE cells. In aim 3 we will test the hypothesis that a Dab2Smad3 interaction is required for the pathogenic effects of TGF-β1 in HBE cells. We anticipate that our studies will lead to novel therapy precisely targeting the pathogenic TGF-β1 activity, to preserve airway integrity, and to promote efficacy of correctors to restore the ∆F508-CFTR function in CF patients. Our studies will also benefit many other patients with common non-CF lung disease.

描述（由适用提供）：高加索人中最常见的隐性疾病（CF）是由编码囊性纤维化跨膜电导调节剂（CFTR）的基因中的突变引起的，一种营地激活的氯离子通道。 CF患者会出现慢性肺部感染和注射，可以部分由白介素（IL）-17A介导，导致支气管扩张，最终导致呼吸衰竭和死亡。 CF与许多其他形式的肺部疾病共享特征，其中感染起着主要作用。 90％的CF患者携带至少一份∆F508等位基因。当前对CF肺部疾病的治疗仅在ΔF508突变患者的CF患者中略有有效。一个关键限制是，大多数CF患者产生高水平的转化生长因子（TGF）-β1。我们发表的工作表明，TGF-β1抑制HBE细胞中的∆F508-CFTR转录，在治疗剂VX-809的上游作用，从而阻止其有效性。高TGF-β1水平也是CF患者炎症的主要原因。这是TGF-β1信号传导是一种主要的内源性途径，除了促进炎症外，还限制了VX-809在CF中的有效性。我们的初步数据证实，VX-809可以逆转TGF-β1CFTR转录的抑制作用，或者IL-17A诱导的炎症细胞因子的分泌。 TGF-β1具有许多稳态效应，包括将愈合和T细胞分化。目前，如何精确靶向TGF-β1的致病作用，而不会损害稳态功能。针对TGF-β1途径中细胞类型特异性和疾病与疾病的活化剂可以作为一种新型的治疗策略，可以选择性地消除CF中TGF-β1的致病性续集。我们已经表明，DAB2（disabled-2）可能在TGF-β1受体下游起作用这种作用，并指导TGF-β1途径中关键介体的核运输，在人支气管上皮（HBE）细胞中SMAD3。我们的中心假设是TGF-β1稳定DAB2-SMAD3相互作用，以增加SMAD3的核输送，从而导致HBE细胞中∆F508-CFTR转录和炎症的表达。 DAB2收藏夹Smad3信号传导，通过VX-809阻止∆F508-CFTR蛋白营救，供应促炎性串扰，并使结果恶化。因此，DAB2-SMAD3界面代表了CF和其他形式的肺部疾病的新型治疗靶标，其中感染是由TGF-β1介导的。在AIM 1中，我们将检验以下假设：DAB2和SMAD3介导TGF-β1在HBE细胞中的致病作用。在AIM 2中检验了DAB2指导专门在HBE细胞中的激活SMAD3的核易位的假设。在AIM 3中，我们将测试以下假设：TGF-β1在HBE细胞中的致病作用需要DAB2SMAD3相互作用。我们预计我们的研究将导致新的治疗精确地靶向致病性TGF-β1活性，以保持气道完整性，并促进校正器的效率以恢复CF患者的∆F508-CFTR功能。我们的研究还将使许多其他常见非CF肺部疾病患者受益。