Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)

 描述(由申请人提供)：肺淋巴管肌瘤病(LAM)是一种罕见的进行性转移性和潜在致命的间质性肺部疾病，主要影响育龄妇女。结节性硬化症复合体1(TSC1)或TSC2抑癌基因突变可诱发LAM。LAM疾病的严重程度与病变淋巴管密度和LAM的生物标志物促淋巴管生成血管内皮生长因子-D(VEGF-D)水平有关。与VEGFR3结合的VEGF-D信号主要表达于淋巴管内皮细胞(LECs)和髓系抑制细胞(MDSCs)。然而，目前尚不清楚血管内皮生长因子D是否仅仅是LAM病的一个标志物。新概念认为，血管内皮生长因子-D可诱导异常淋巴管生成和肿瘤向淋巴管的侵袭。肿瘤还通过使用免疫抑制的MDSCs来利用主动的免疫逃避机制。由于与MDSCs分泌的血管内皮生长因子-D有关，MDSCs的侵袭与淋巴管生成密切相关。该项目的中心假设是，在LAM中，依赖TSC2的VEGF-D上调诱导MDSC募集和异常淋巴管生成，通过抑制T细胞功能来调节适应性免疫。我们的观察还提出了一个翻译假说，即在LECs和MDSCs中通过药物靶向VEGFR3信号将消除异常的淋巴管生成和MDSC的免疫抑制功能，并将为防止LAM的细胞外基质重塑和肺实质的破坏提供辅助治疗。为了验证我们的假设，我们将特别问：在目标1：血管内皮生长因子-D是否促进了LAM细胞的侵袭性和淋巴管的异常生成？目标2：骨髓间充质干细胞是否导致LAM免疫抑制？在目标3中：靶向LECs和MDSCs的血管内皮生长因子-D信号是否有助于消除LAM中MDSCs的免疫抑制功能、异常淋巴管生成和肺破坏？在这个项目中，我们提出了一种新的范式，即MDSCs在LAM中发挥免疫调节作用。总之，我们的研究将通过以下方面影响LAM的基础和翻译研究：1)确定MDSCs免疫抑制功能的机制；2)确定淋巴管内皮细胞在调节LAM细胞侵袭性中的新作用；以及3)为LAM潜在的新分子靶点和辅助治疗提供见解。我们的研究还将提供新的见解，促进我们对LAM病变的免疫生物学的理解，并可能找出LAM中淋巴管生成异常与疾病严重程度相关的主要原因，同时补充现有的治疗方法与免疫疗法，以开发LAM的治愈方法。

 DESCRIPTION (provided by applicant): Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive metastatic and potentially fatal interstitial lung disease, affects primarily women of childbearing age. Mutations of the Tuberous Sclerosis Complex 1 (TSC1) or TSC2 tumor suppressor genes induce LAM. LAM disease severity correlates with the degree of pathogenic lymphatic vessel density and serum levels of the pro-lymphangiogenic vascular endothelial growth factor-D (VEGF-D), a biomarker of LAM. VEGF-D signals by binding to VEGFR3 predominantly expressed on lymphatic endothelial cells (LECs) and myeloid-derived suppressor cells (MDSCs). Little is known, however, whether VEGF-D is merely a marker of LAM disease. Emerging concepts posit that the VEGF-D induces abnormal lymphangiogenesis and tumor invasion towards lymphatics. Tumors also employ active mechanisms of immune evasion by using immunosuppressive MDSCs. Because of the connection with VEGF-D being secreted by MDSCs, MDSCs infiltration correlates with lymphangiogenesis. This project centers on the hypothesis that in LAM, the TSC2-dependent upregulation of VEGF-D induces MDSC recruitment and abnormal lymphangiogenesis that modulate adaptive immunity by suppressing T cell function. Our observations also posits a translational hypothesis that pharmacological targeting of VEGFR3 signaling in LECs and MDSCs will abrogate abnormal lymphangiogenesis, and MDSC immunosuppressive function and will provide adjuvant therapy for preventing extracellular matrix remodeling and destruction of lung parenchyma in LAM. To test our hypothesis, we will specifically ask: In Aim 1: Does VEGF-D promote LAM cell invasiveness and abnormal lymphangiogenesis in LAM? In Aim 2: Do MDSCs induce immune suppression in LAM? and in Aim 3: Will therapeutic targeting of VEGF-D signaling in LECs and MDSCs be beneficial in abrogating the immunosuppressive function of MDSCs, abnormal lymphangiogenesis and lung destruction in LAM? In this project we suggest a new paradigm that MDSCs serve an immunomodulatory role in LAM. Collectively, our studies will impact basic and translational LAM research by: 1) determining mechanisms of immunosuppressive function of MDSCs; 2) defining a new role of lymphatic endothelium in regulating LAM cell invasiveness; and 3) providing insights about potential novel molecular targets and adjuvant therapeutics in LAM. Our study will also provide new insights and advance our understanding of immunobiology of LAM lesions, and may identify a major reason why abnormal lymphangiogenesis in LAM correlates with the disease severity, while complementing current treatments with immunotherapy to develop a cure for LAM.