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Role of folliculin (FLCN) in lung cell survival

滤泡素 (FLCN) 在肺细胞存活中的作用

基本信息

批准号：
8620705
负责人：
VERA P KRYMSKAYA
金额：
$ 44.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8620705
关键词：
5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Actins Adaptor Signaling Protein Affect Airway Resistance Alveolar Alveolar Cell Anoikis Apoptosis Binding Biochemical Birt-Hogg-Dube Syndrome Bronchoalveolar Lavage Cell Communication Cell Death Cell Polarity Cell Survival Cells Cellular Morphology Complex Cyst Cystic kidney Cytoskeleton DNA Sequence Rearrangement Data Disease Distal Down-Regulation Energy Metabolism Epithelial Cells Epithelium Etiology Folliculin Goals Human In Vitro Induced Mutation Kidney Neoplasms Link Lung Lung diseases Maintenance Metabolism Molecular Molecular Target Mus Null Lymphocytes Phosphorylation Pneumothorax Preclinical Testing Production Proteins Publishing Pulmonary Surfactants Respiratory physiology Role Signal Pathway Signal Transduction Small Interfering RNA Testing Transgenic Mice Transgenic Organisms Tuberous sclerosis protein complex Tumor-Suppressor Gene Inactivation alveolar destruction base cell type glucose transport glucose uptake in vivo insight mTOR protein novel novel therapeutic intervention pulmonary function recombinase small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Cystic airspace enlargement and spontaneous pneumothorax are major pathological manifestations Birt-Hogg- Dube (BHD) syndrome. Although the etiology of this disease is not known, lung cysts in BHD are linked to autosomal dominant mutational inactivation of tumor suppressor gene folliculin (FLCN). FLCN, a 64-kDa ubiquitously expressed protein with high homology throughout species that lacks apparent functional domain, through adaptor proteins FNIP1/2, binds the 5'-AMP-activated protein kinase (AMPK). Little, however, is known about a role of folliculin (FLCN) in lung cell survival. Our in vitro and in vivo studies demonstrate that FLCN is required for lung cell survival by acting within 5'-AMP-activated protein kinase (AMPK) - tuberous sclerosis complex 2 (TSC2) - mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. To fill a gap in the current understanding of airspace enlargement, we have restricted the scope of this proposal to one testable, central hypothesis that FLCN is required for lung cell survival. To test our hypothesis, in Aim 1, we will determine whether FLCN is required for lung epithelial cell survival in vivo using new transgenic FLCNf/f:SP-C- Cre mice generated in PI's lab. Targeted conditional inducible deletion of FLCN in SP-C-expressing lung epithelial cells will allow us to identify the specific lung epithelial cell type affected by FLCN loss that promotes alveolar space enlargement. In Aim 2 we will examine whether FLCN is required for maintenance of epithelial cell morphology and metabolism. In Aim 3, we will determine FLCN role in regulating activities of Akt and AMPK kinases, and whether pharmacological activation of AMPK will rescue lung epithelial cell survival with targeted inducible deletion of FLCN in FLCNf/f:SP-C-Cre mice. These studies will identify the role of FLCN in lung cell survival, provide insights into the cellular an molecular mechanism of lung epithelial cell-cell contacts, actin cytoskeleton, and metabolism regulated by FLCN. These studies will also establish a mechanistic link between loss of FLCN and cystic airspace enlargement by using our unique novel FLCNf/f:SP- C-Cre transgenic mice and identify potential molecular target(s) for novel therapeutic approaches to treat BHD.

描述（申请人提供）：囊性空域扩大和自发性气胸是BHD综合征的主要病理表现。虽然这种疾病的病因尚不清楚，但BHD的肺囊肿与肿瘤抑制基因滤泡蛋白（FLCN）的常染色体显性突变失活有关。FLCN是一种64 kda的蛋白，在缺乏明显功能域的物种中普遍表达，具有高度同源性，通过衔接蛋白FNIP1/2结合5'- amp活化蛋白激酶（AMPK）。然而，对于滤泡蛋白（FLCN）在肺细胞存活中的作用所知甚少。我们的体外和体内研究表明，FLCN是肺细胞存活所必需的