Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)

肺淋巴管平滑肌瘤病 (LAM) 中的淋巴管生成

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：一种罕见的进行性转移性和潜在致命的间质性肺疾病的肺淋巴结肌瘤病（LAM）会影响生育年龄的主要妇女。结节硬化症复合物1（TSC1）或TSC2肿瘤抑制基因的突变诱导LAM。 LAM疾病的严重程度与致病性血管生成血管内皮生长因子-D（VEGF-D）（LAM的生物标志物）的致病性淋巴管密度和血清水平相关。 VEGF-D信号通过与淋巴内皮细胞（LEC）和髓样衍生的抑制细胞（MDSC）（MDSC）结合，主要表达为VEGFR3。然而，知之甚少，VEGF-D是否仅仅是LAM疾病的标志。新兴概念肯定，VEGF-D诱导异常的淋巴生成和肿瘤侵袭淋巴管。肿瘤还具有免疫抑制MDSC的活性机制。由于与MDSC分泌的VEGF-D的联系，MDSCS浸润与淋巴管生成有关。该项目以这样的假设为中心：在LAM中，VEGF-D的TSC2依赖性更新诱导MDSC募集和异常的淋巴管生成，可通过抑制T细胞功能来调节适应性免疫学。我们的观察结果还提出了一种翻译假设，即在LEC和MDSC中对VEGFR3信号的药物靶向将消除异常的淋巴管生成和MDSC免疫抑制功能，并将提供可调节的疗法，以防止细胞外基质重塑和破坏Lung parephemyma in Lam in lam in lam in lam。为了检验我们的假设，我们将特别提出：在AIM 1：VEGF-D是否促进LAM中的LAM细胞侵入性和异常淋巴管生成？在AIM 2中：MDSC是否在LAM中诱导免疫调节抑制？在AIM 3中：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中淋巴管生成异常和肺破坏的异常？在这个项目中，我们建议一种新的范式，即MDSC在LAM中起免疫调节作用。总的来说，我们的研究将对基本和转化的LAM研究影响：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）提供有关潜在的新分子靶标和可调疗法的见解。我们的研究还将提供新的见解，并提高我们对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，同时通过免疫疗法进行治疗以开发LAM治疗的当前治疗。