Pathogenesis and Treatment of Kaposiform Lymphangiomatosis

卡波西样淋巴管瘤病(KLA)是一种破坏性的先天性淋巴异常，其存活率为51% 5年，总体为34%。KLA患者患有胸腔和心脏积液以及凝血障碍，导致 高发病率和高死亡率。KLA的组织病理学特征是病变中含有纺锤体簇- 形态内皮细胞伴随畸形淋巴管，通常位于肺、脾、腹部、 和/或肝脏。这些特有的梭形内皮细胞的作用、来源和功能尚不清楚。明确的 KLA的诊断往往由于复杂的症状和活检的风险而延误 凝血障碍。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，我们首先发现 KLA的血液生物标记物，血管生成素-2(Ang-2)，可能为了解潜在的 疾病机制。血管生成素-2作为促血管生成因子在KLA患者中高度升高 且随着西罗莫司的治疗而降低，提示KLA中Ang-2的异常调节依赖于 MTOR信令。对KLA发病机制的其他可能见解来自于对一种 患者皮损组织中NRAS Q61R的体细胞突变。Q61R是一种NRAS激活突变，在&gt；20% 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位于血管紧张素转换酶的上游。 2诱导KLA皮损内皮细胞形态呈梭形。拟议的研究将确定 参与这一调节的过程和途径有助于推动对KLA发病机制的理解 往前走。这项提议的目的是检验NRAS Q61R介导发病机制的假设 KLA通过增加MAPK和PI3K-AKT-mTOR信号，诱导梭形内皮细胞， 上调Ang-2的表达，从而驱动异常的淋巴管生成。我们已经开发出 独特的体外和体内模型来验证这一假说和来自我们实验室的初步数据 支持这一拟议的机制，并论证了我们方法的可行性。这些研究将 解决KLA中的关键知识缺口。我们将测试目前治疗以来的新的治疗靶点， 西罗莫司充其量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，寻找新的治疗靶点。我们处于独特的位置，拥有 专业知识和实验模型在手。

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.