Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)

肺淋巴管平滑肌瘤病 (LAM) 中的淋巴管生成

• 批准号: 9078976
• 负责人: VERA P KRYMSKAYA
• 金额: $ 65.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078976
• 关键词: Adjuvant; Adjuvant Therapy; Affect; Binding; Biological Markers; Blood Vessels; Bone Marrow; CCL2 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cell physiology; Cells; Complement; Complement Factor D; Data; Development; Disease; Endothelial Growth Factors; Exhibits; Extracellular Matrix; FDA approved; FRAP1 gene; Female of child bearing age; Gelatinase B; Growth; Human; Immune; Immunobiology; Immunocompetent; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Interleukin-6; Interstitial Lung Diseases; KDR gene; Lesion; Lung; Lung Lymphangioleiomyomatosis; Lung diseases; Lymphangiogenesis; Lymphangioleiomyomatosis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic vessel; Mediator of activation protein; Modeling; Molecular Target; Mus; Mutation; Myelogenous; Process; Receptor Signaling; Recruitment Activity; Research; Role; Serum; Severity of illness; Signal Transduction; Structure of parenchyma of lung; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TSC2 gene; Testing; Therapeutic; Tuberous sclerosis protein complex; Tumor Cell Invasion; Tumor Immunity; Tumor Suppressor Genes; Up-Regulation; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; adaptive immunity; alveolar destruction; cell growth; density; insight; interstitial; novel; preclinical study; prevent; public health relevance; small molecule inhibitor; therapeutic target; tumor

 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.

 描述（由申请人提供）：肺淋巴管平滑肌瘤病（LAM）是一种罕见的进行性转移性且可能致命的间质性肺病，主要影响育龄妇女。结节性硬化症复合体 1 (TSC1) 或 TSC2 肿瘤抑制基因的突变会诱导 LAM。 LAM 疾病的严重程度与致病性淋巴管密度程度和促淋巴管生成血管内皮生长因子-D (VEGF-D) 的血清水平相关，VEGF-D 是 LAM 的生物标志物。 VEGF-D 通过与主要在淋巴内皮细胞 (LEC) 和骨髓源性抑制细胞 (MDSC) 上表达的 VEGFR3 结合来发出信号。然而，人们对 VEGF-D 是否仅仅是 LAM 疾病的标志物知之甚少。新出现的概念认为 VEGF-D 会诱导异常的淋巴管生成和肿瘤对淋巴管的侵袭。肿瘤还通过使用免疫抑制性 MDSC 来采用主动的免疫逃避机制。由于与 MDSC 分泌的 VEGF-D 有关，MDSC 浸润与淋巴管生成相关。该项目的中心假设是，在 LAM 中，TSC2 依赖性 VEGF-D 上调会诱导 MDSC 募集和异常淋巴管生成，从而通过抑制 T 细胞功能来调节适应性免疫。我们的观察还提出了一个转化假设，即 LEC 和 MDSC 中 VEGFR3 信号传导的药理学靶向将消除异常的淋巴管生成和 MDSC 免疫抑制功能，并将为防止 LAM 中细胞外基质重塑和肺实质破坏提供辅助治疗。为了检验我们的假设，我们将特别提出以下问题：在目标 1 中：VEGF-D 是否会促进 LAM 细胞侵袭和 LAM 中异常淋巴管生成？目标 2：MDSC 是否会诱导 LAM 中的免疫抑制？目标 3：LEC 和 MDSC 中 VEGF-D 信号传导的治疗靶向是否有益于消除 MDSC 的免疫抑制功能、LAM 中的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例，即 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 的免疫抑制功能机制； 2）定义淋巴管内皮在调节LAM细胞侵袭性中的新作用； 3) 提供有关 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增进我们对 LAM 病变免疫生物学的理解，并可能确定 LAM 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当前的治疗方法，以开发 LAM 的治愈方法。