Pathogenesis and Treatment of Kaposiform Lymphangiomatosis

Kaposiform淋巴管瘤病（KLA）是一种毁灭性的先天性淋巴管异常， 5年，占总人数的34%。KLA患者患有胸腔积液和心脏积液以及凝血病，导致 高发病率和死亡率。KLA的组织病理学特征是含有梭形簇的病变， 典型地在肺、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。明确 KLA的诊断通常由于复杂的症状和活检的风险而延迟， 凝血病作为使用西罗莫司（雷帕霉素; mTOR抑制剂）的临床试验的一部分，我们首先确定了 KLA的血液生物标志物血管生成素-2（ANG-2），可能为了解KLA的潜在机制提供重要见解。 疾病机制。作为促血管生成因子的ANG-2在KLA患者中高度升高 西罗莫司治疗后降低，表明KLA中ANG-2的失调依赖于 mTOR信号传导。对KLA发病机制的其他可能的见解来自于对一种 在来自患者的病变组织中的体细胞突变NRAS Q61 R。Q61 R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 Q61 R是ANG-1的上游。 2诱导KLA病变的梭形内皮细胞形态。拟议的研究将确定 参与这种调节的过程和途径，并有助于理解KLA发病机制 性新该提案的目的是检验NRAS Q61 R介导发病机制的假设。 通过增加MAPK和PI 3 K-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。我们已经开发 独特的体外和体内模型来测试这一假设和我们实验室的初步数据， 支持这一拟议机制，并证明我们的做法是可行的。这些研究将 解决科索沃解放军的重大知识差距。我们将测试新的治疗目标， 西罗莫司最多只能诱导部分临床反应。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。我们处于独特的位置， 专业知识和实验模型。

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.