Urokinase-type plasminogen activator (uPA) in pathogenesis of lymphangioleiomyomatosis (LAM)

尿激酶型纤溶酶原激活剂 (uPA) 在淋巴管平滑肌瘤病 (LAM) 发病机制中的作用

基本信息

批准号：
10323035
负责人：
VERA P KRYMSKAYA
金额：
$ 44.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323035
关键词：
Ablation Address Adhesions Affect Attenuated Basic Science Binding Blood Vessels C-terminal Cell Nucleus Cell Proliferation Cells Characteristics Complex Cystic Lesion Data Diagnosis Disease Enzymes FRAP1 gene Failure Genes Genetic Genetic Transcription Germ-Line Mutation Growth Human Immunosuppression In Vitro Individual Interruption KDR gene Knockout Mice Kringles Lesion Lung Lung Lymphangioleiomyomatosis Lung Neoplasms Lung diseases Lung nodule Lymphangiogenesis Lymphangioleiomyomatosis Lymphatic Lymphatic Endothelial Cells Lymphatic System Malignant Neoplasms Mediating Modeling Molecular Molecular Target Mus N-terminal Neoplasms Nodule Nuclear Translocation Null Lymphocytes Pathogenesis Pathway interactions Permeability Pharmacology Phenotype Plasmin Premenopause Proteolysis Role Serine Protease Serum Severities Signal Transduction Sirolimus Smooth Muscle Somatic Mutation Structure of parenchyma of lung Syndrome TSC1 gene TSC2 gene Tissues Translational Research Tuberous Sclerosis Tumor Suppressor Proteins Up-Regulation Urokinase Vascular Endothelial Cell Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor D Withdrawal Woman angiogenesis base cell growth effusion in vivo inhibitor insight lung lesion lymphatic development lymphatic malformations mTOR inhibition migration mouse model neoplastic neoplastic cell novel novel marker overexpression pulmonary function receptor self-renewal side effect therapeutic target tumor tumor growth tumorigenic

项目摘要

SUMMARY Lymphangioleiomyomatosis (LAM) is a progressive neoplastic lung disease associated with inactivation of tuberous sclerosis complex 1/2 (TSC1/2) genes and upregulation of mTOR signaling. LAM is characterized by proliferative lung nodules that destroy surrounding parenchyma and aberrant lymphangiogenesis causing chylous effusions. LAM lesions express high levels of urokinase plasminogen activator (uPA), an enzyme implicated in the proliferation and spread of cancers, but not its primary inhibitor (PAI-1). We demonstrate that genetic ablation of TSC2 leads directly to upregulation of uPA but not PAI-1. Deletion of uPA attenuates the growth of TSC2-null lung tumors and inhibits aberrant lymphangiogenesis in vivo. Surprisingly, inhibition of mTORC1 by rapamycin, currently used to treat LAM, further up- regulates uPA and dramatically upregulates its receptor (uPAR), but not PAI-1, in TSC2- compromised cells, consistent with its failure to eradicate the disease. In this proposal we will examine the mechanism by which loss of TSC leads to upregulation of uPA expression and activity and the consequences of uPA upregulation on the proliferation of LAM cells and the development of lymphatics in vitro and in vivo. In Aim 1, we will delineate the pathway by which loss of TSC induces uPA and examine how this is amplified by inhibition of mTORC1. In Aim 2, we will examine how uPA and VEGF-D secreted by TSC2-null LAM cells promotes uPA overexpression and subsequent growth, migration, lymphangiongesis and growth of LAM lung lesions. We will delineate the contribution of specific uPA domains that mediate tissue proteolysis, intracellular signaling and nuclear translocation/gene transcription. In Aim 3, will determine whether blocking upregulation of uPA will act in concert with inhibition of mTORC1 to control the growth TSC2-null tumors and aberrant lymphangiongesis in a murine model of LAM. The results of this study will provide new insights into the pathogenesis of LAM, advance our understanding of the mechanism by which uPA promotes neoplasia, and potentially identify a novel biomarker and auxiliary therapeutic target for the diagnosis and management of LAM.

概括淋巴血管肌瘤病（LAM）是一种进行性肿瘤疾病结节性硬化症复合物1/2（TSC1/2）基因的失活和MTOR上调信号。 lam的特征是增生性肺结节，破坏周围的周围实质和异常淋巴管生成，导致胆囊积液。林病变表达高水平的尿激酶纤溶酶原活化剂（UPA），一种与增殖有关的酶和癌症的传播，而不是其主要抑制剂（PAI-1）。我们证明了遗传 TSC2的消融直接导致UPA的上调，而不是PAI-1。删除UPA衰减 TSC2-NULL肺肿瘤的生长并抑制体内异常淋巴管生成。令人惊讶的是，雷帕霉素对MTORC1的抑制作用，目前用于治疗LAM，进一步在TSC2-中，调节UPA并大大上调其受体（UPAR），但不是PAI-1 受损的细胞，与其无法消除该疾病一致的细胞。在这个建议中，我们将检查TSC丢失导致UPA表达的上调和活性和UPA上调对LAM细胞和的后果体外和体内淋巴管的发展。在AIM 1中，我们将描述该路径 TSC的丢失诱导UPA并检查如何通过抑制MTORC1扩大。在AIM 2中，我们将研究TSC2-NULL LAM细胞分泌的UPA和VEGF-D如何促进UPA 过表达和随后的生长，迁移，淋巴管和肺肺的生长病变。我们将描述介导组织的特定UPA结构域的贡献蛋白水解，细胞内信号传导和核易位/基因转录。在AIM 3中，将确定阻止UPA上调是否会与抑制MTORC1一起起作用控制LAM的鼠模型中的生长TSC2无效肿瘤和异常淋巴管。这项研究的结果将为LAM的发病机理提供新的见解，促进我们的了解UPA促进肿瘤的机制，并可能识别用于诊断和管理LAM的新型生物标志物和辅助治疗靶标。