Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)

 描述（由申请方提供）：肺淋巴管平滑肌瘤病（LAM）是一种罕见的进行性转移性和潜在致死性间质性肺病，主要累及育龄女性。多发性硬化症复合体1（TSC 1）或TSC 2肿瘤抑制基因的突变可诱导LAM。LAM疾病的严重程度与致病性淋巴管密度的程度和促淋巴管生成血管内皮生长因子-D（VEGF-D）（LAM的生物标志物）的血清水平相关。VEGF-D通过与主要在淋巴管内皮细胞（LEC）和髓源性抑制细胞（MDSC）上表达的VEGFR3结合而发出信号。然而，很少有人知道VEGF-D是否仅仅是LAM疾病的标志物。新的观点认为VEGF-D诱导异常淋巴管生成和肿瘤向淋巴细胞的侵袭。肿瘤还通过使用免疫抑制性MDSC采用免疫逃避的主动机制。由于与MDSC分泌的VEGF-D相关，MDSC浸润与淋巴管生成相关。该项目的中心假设是，在LAM中，VEGF-D的TSC 2依赖性上调诱导MDSC募集和异常淋巴管生成，其通过抑制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LEC和MDSC中VEGFR3信号传导的药理学靶向将消除异常淋巴管生成和MDSC免疫抑制功能，并将提供预防LAM中细胞外基质重塑和肺实质破坏的辅助治疗。为了验证我们的假设，我们将特别提出以下问题：在目标1中：VEGF-D是否促进LAM细胞的侵袭性和LAM中的异常淋巴管生成？目的2：MDSC是否在LAM中诱导免疫抑制？目标3：在LEC和MDSC中靶向VEGF-D信号传导的治疗是否有利于消除LAM中MDSC的免疫抑制功能、异常淋巴管生成和肺破坏？在这个项目中，我们提出了一个新的范例，MDSC在LAM中发挥免疫调节作用。总的来说，我们的研究将通过以下方式影响基础和转化LAM研究：1）确定MDSC免疫抑制功能的机制; 2）定义淋巴内皮在调节LAM细胞侵袭性中的新作用; 3）提供关于LAM中潜在的新型分子靶点和辅助治疗的见解。我们的研究还将提供新的见解，并促进我们对LAM病变免疫生物学的理解，并可能确定LAM中异常淋巴管生成与疾病严重程度相关的主要原因，同时用免疫疗法补充目前的治疗方法，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.