Pathogenesis and Treatment of Kaposiform Lymphangiomatosis

卡波西样淋巴管瘤病的发病机制及治疗

基本信息

批准号：
10360838
负责人：
TIMOTHY DAVID LE CRAS
金额：
$ 61.83万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360838
关键词：
3-Dimensional Abdomen Address Affect Angiogenic Factor Angiopoietin-2 Antibodies Automobile Driving Biological Assay Biological Markers Biopsy Blood Blood Coagulation Disorders Blood Vessels Cardiac Cells Cellular Morphology Characteristics Chemicals Chest Child Clinical Clinical Trials Complex Cyst Cytoplasmic Granules DNA Sequence Alteration Data Diagnosis Diet Disease Doxycycline Endothelial Cells Erythrocytes Experimental Models FRAP1 gene Film Functional disorder Genetic Goals Hand Head Hemorrhage Hemosiderin Histology Histopathology Human Image Implant In Vitro Knowledge Laboratories Left Lesion Liver Lung Lymphangiogenesis Lymphangiography Lymphangiomatosis Lymphatic MAP Kinase Gene MEKs Magnetic Resonance Imaging Malignant Neoplasms Manuscripts Measures Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutation Neuroblastoma Organ Pathogenesis Pathway interactions Patients Phosphotransferases Pleural Pleural effusion disorder Positioning Attribute Pre-Clinical Model Process Proteomics Proto-Oncogene Proteins c-akt Pulmonary artery structure Radiology Specialty Regulation Relapse Retroperitoneal Space Risk Role Signal Pathway Signal Transduction Sirolimus Somatic Mutation Spindle Endothelial Cell Spleen Stains Structure Symptoms TEK gene Tail Testing Tissues United States National Institutes of Health Veins Xenograft Model Xenograft procedure autocrine effusion experience feeding in vitro Model in vivo Model inhibitor insight lymphatic malformations lymphatic vessel mTOR Inhibitor malformation melanoma migration mortality mutant new therapeutic target novel therapeutics overexpression paracrine response small hairpin RNA soft tissue subcutaneous transcriptome sequencing young adult

项目摘要

Kaposiform lymphangiomatosis (KLA) is a devastating congenital lymphatic anomaly with a 51% survival at 5 years, and 34% overall. KLA patients suffer from pleural and cardiac effusions and coagulopathy leading to the high morbidity and mortality. The histopathology of KLA features lesions containing clusters of spindle- shaped endothelial cells accompanying malformed lymphatic vessels typically in the lungs, spleen, abdomen, and/or liver. The role, origin and function of these characteristic spindled endothelial cells is unclear. Definitive diagnosis of KLA is often delayed due to the complex symptoms and the risks of biopsy due to the coagulopathy. As part of a clinical trial using sirolimus (rapamycin; mTOR inhibitor) we were the first to identify a blood biomarker for KLA, angiopoietin-2 (ANG-2), that may provide important insights into the underlying disease mechanisms. ANG-2, which can act as a pro-angiogenic factor, was highly elevated in KLA patients and decreased with sirolimus treatment suggesting that dysregulation of ANG-2 in KLA is dependent on mTOR signaling. Additional possible insights into pathogenesis of KLA have come from the identification of a somatic mutation NRAS Q61R in lesion tissue from patients. Q61R is an NRAS activating mutation in >20% of melanomas and other cancers; however, its role in human endothelial cells and vascular malformations is unclear. Our preliminary studies with human endothelial cells suggest that NRAS Q61R is upstream of ANG- 2 and induces the spindled endothelial cell morphology in KLA lesions. Proposed studies will identify the processes and pathways involved in this regulation and help move the understanding of KLA pathogenesis forward. The goal of this proposal is to test the hypothesis that NRAS Q61R mediates the pathogenesis of KLA by increasing MAPK and PI3K-AKT-mTOR signaling, inducing spindled endothelial cells, upregulating ANG-2 expression, and so driving abnormal lymphangiogenesis. We have developed unique in vitro and in vivo models to test this hypothesis and preliminary data from our laboratory strongly supports this proposed mechanism and demonstrates the feasibility of our approach. These studies will address a critical knowledge gap in KLA. We will test new therapeutic targets since the current treatment, sirolimus, at best only induces a partial clinical response. Our long-term goals are to elucidate the cellular and molecular pathogenesis of KLA and identify new therapeutic targets. We are uniquely positioned having the expertise and experimental models in hand.

卡波西样淋巴管瘤病 (KLA) 是一种破坏性的先天性淋巴管异常，其存活率为 51% 5 年，总体 34%。 KLA 患者患有胸腔积液和心脏积液以及凝血障碍，导致高发病率和死亡率。 KLA 的组织病理学特征是含有纺锤体簇的病变。畸形的内皮细胞伴随着畸形的淋巴管，通常出现在肺、脾、腹部、和/或肝脏。这些特征性梭形内皮细胞的作用、起源和功能尚不清楚。权威的由于复杂的症状和活检的风险，KLA 的诊断经常被延迟凝血病。作为使用西罗莫司（雷帕霉素；mTOR 抑制剂）临床试验的一部分，我们是第一个发现 KLA 血管生成素-2 (ANG-2) 的血液生物标志物，可能为了解潜在的疾病提供重要见解疾病机制。 ANG-2 可以作为促血管生成因子，在 KLA 患者中高度升高并随西罗莫司治疗而减少，表明 KLA 中 ANG-2 的失调取决于 mTOR 信号传导。对 KLA 发病机制的更多可能见解来自于对患者病变组织中的体细胞突变 NRAS Q61R。 Q61R 是>20% 的 NRAS 激活突变黑色素瘤和其他癌症；然而，它在人类内皮细胞和血管畸形中的作用是不清楚。我们对人内皮细胞的初步研究表明 NRAS Q61R 是 ANG- 的上游 2并诱导KLA损伤中的梭形内皮细胞形态。拟议的研究将确定参与该调节的过程和途径，有助于加深对 KLA 发病机制的理解向前。该提案的目的是检验 NRAS Q61R 介导发病机制的假设通过增加 MAPK 和 PI3K-AKT-mTOR 信号传导，诱导梭形内皮细胞，上调 ANG-2 表达，从而驱动异常淋巴管生成。我们开发了独特的体外和体内模型有力地检验了这一假设以及我们实验室的初步数据支持这一提议的机制并证明了我们方法的可行性。这些研究将解决 KLA 中的关键知识差距。自目前的治疗以来，我们将测试新的治疗靶点，西罗莫司最多只能引起部分临床反应。我们的长期目标是阐明细胞和 KLA 的分子发病机制并确定新的治疗靶点。我们处于独特的地位，拥有现有的专业知识和实验模型。