AIBP Mediates a Novel Interplay between Cholesterol Metabolism and Lymphangiogenesis

AIBP 介导胆固醇代谢和淋巴管生成之间的新相互作用

基本信息

批准号：
9247254
负责人：
Longhou Fang
金额：
$ 52.92万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247254
关键词：
Address Adipose tissue Affect Angiopoietins Apolipoprotein A-I Binding Proteins Biological Availability Blood Vessels Caveolae Cell Culture System Cell membrane Characteristics Cholesterol Cholesterol Homeostasis Congenital Disorders Data Development Disease Endothelial Cells Endothelium Ephrin-B2 Family member Fibrosis Fluorescence Functional disorder Generations Genes Growth Homeostasis Human Impairment In Vitro Intercellular Fluid KDR gene Limb structure Lipids Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic vessel Lymphedema Maintenance Mediating Membrane Membrane Microdomains Modeling Molecular Mus Nature Patients Play Pre-Clinical Model Proteins Recombinants Regulation Reporting Role Route Scaffolding Protein Severities Signal Transduction Swelling Testing Therapeutic Effect Tissues Transforming Growth Factor beta Transgenic Organisms VEGFC gene Vascular Endothelial Growth Factor Receptor-3 Venous Zebrafish angiogenesis caveolin 1 gain of function improved insight interstitial laurdan lymphatic drainage migration mouse model notch protein novel novel therapeutic intervention novel therapeutics paracrine protein expression public health relevance receptor restoration stem targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Lymphedema is a debilitating disease that may be caused by congenital disorder or acquired damage to lymphatic vessels. Patients with this disease manifest edematous swelling in the affected tissue because of excessive protein- and lipid-rich fluid in the interstitial space. Further tissue remodeling will result in adipose accumulation and fibrosis of the ailing tissue; treatment for this disease is so far limited. Recently, emerging studies have indicated that augmenting lymphangiogenesis, which results in generation of new lymphatic vessels, might represent a new therapeutic approach. Lymphangiogenesis is controlled by the VEGFC/VEGFR3 axis-induced proliferation and migration of lymphatic endothelial cells derived from the venous precursors. We recently demonstrated that apoA-I binding protein (AIBP) and caveolae/lipid rafts regulate angiogenesis. In this proposal, we sought to elucidate the role of AIBP and caveolae in lymphangiogenesis. Our preliminary studies suggest that AIBP and caveolae regulate VEGFR3 signaling and lymphangiogenesis. We will test the hypothesis that AIBP enhances VEGFR3 signaling by increasing cholesterol efflux and reducing the inhibition of caveolin-1 within caveolae. To this end, we will use in vitro lymphatic endothelial cell culture system, different transgenic zebrafish lines and genetically modified mouse models. Our studies on AIBP will contribute to the development of new therapies facilitating lymphatic vessel growth and restoring lymphatic functions in diseases caused by dysfunctional lymphatics.

描述（由申请人提供）：淋巴水肿是一种使人衰弱的疾病，可能是由先天性淋巴管疾病或后天性淋巴管损伤引起的，由于间质中富含蛋白质和脂质的液体过多，因此患者会出现受影响的组织水肿。进一步的组织重塑将导致患病组织的脂肪堆积和纤维化；迄今为止，新的研究表明，增加淋巴管生成是有限的。在新淋巴管的生成中，淋巴管生成可能是由 VEGFC/VEGFR3 轴诱导的源自静脉前体的淋巴内皮细胞的增殖和迁移控制的。在本提案中，我们试图阐明 AIBP 和小窝在淋巴管生成中的作用。小窝调节 VEGFR3 信号传导和淋巴管生成我们将测试 AIBP 通过增加胆固醇流出和减少小窝内小窝蛋白 1 的抑制来增强 VEGFR3 信号传导的假设为此，我们将使用体外淋巴内皮细胞培养系统、不同的转基因斑马鱼。我们对 AIBP 的研究将有助于开发促进淋巴管生长和恢复功能性淋巴管引起的疾病的淋巴功能的新疗法。