Perivascular macrophages endothelial interactions at the blood labyrinth barrier

血管周围巨噬细胞在血迷路屏障处的内皮相互作用

• 批准号: 8500225
• 负责人: Xiaorui Shi
• 金额: $ 18.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500225
• 关键词: Address; Adherens Junction; Affect; Autoimmune Process; Basement membrane; Blood; CD11b Antigens; Cell Culture Techniques; Cell Line; Cells; Cochlea; Coculture Techniques; Coupled; Development; Disease; Electrical Resistance; Endothelial Cells; Epithelial; Fluid Balance; Functional disorder; Goals; Green Fluorescent Proteins; Hearing problem; Herpes zoster disease; Human; ITGAM gene; Immunofluorescence Immunologic; In Vitro; Ion Transport; Ions; Labyrinth; Labyrinthitis; Lead; Link; Measures; Mediating; Meniere' s Disease; Meningitis; Modeling; Molecular; Mono-S; Movement; Mus; Pericytes; Permeability; Pharmacotherapy; Physiological; Physiology; Pigments; Platelet Factor 4; Process; Proteins; Research; Rewards; Risk Factors; Role; Small Interfering RNA; Stria Vascularis; System; Testing; Tight Junctions; Time; Tracer; Transfection; Transgenic Mice; Transmission Electron Microscopy; Vascular Permeabilities; Vesicle; Water; Work; base; blood treatment; cadherin 5; diphtheria toxin receptor; foot; hearing impairment; in vivo; in vivo Model; inhibitor/antagonist; inner ear diseases; innovation; macrophage; molecular mass; monolayer; mouse model; occludin; programs; promoter; protein expression; solute

DESCRIPTION (provided by applicant): The blood-labyrinth barrier (BLB) in the stria vascularis of the cochlea maintains endocochlear potential, ion transport, and fluid balance in the inner ear. Disruption of the BLB has long been considered a major etiologic factor in a variety of hearing disorders, including autoimmune inner ear disease, Meniere's disease, meningitis-associated labyrinthitis, and several genetically-linked diseases. Despite the importance of the BLB, however, the mechanisms that control BLB permeability remain largely unknown. A recent study from our lab unexpectedly found a large number of perivascular resident macrophage (PVMs) in the BLB, in addition to endothelial cells (ECs), basement membrane, and surrounding pericytes. The PVMs are in close contact with vessels through cytoplastic processes-end-feet-which contain a large number of vesicles and transporters. We hypothesize the PVMs and ECs are physiologically coupled for control of water and ion movement in the stria vascularis. In this project, we ask if PVMs contribute to the integrity of th BLB. If so, do PVMs control BLB integrity by affecting expression of tight and adherens junction proteins? Is the control mediated by pigment epithelial-derived factor? To test the hypothesis, we established a new primary EC and PVM cell co-culture model which we will use in association with a transgenic mouse model. The transgenic mice encode a diphtheria toxin receptor providing a system for transient depletion of PVMs. In addressing PVM control of BLB integrity, the proposed work will significantly enhance our understanding of the BLB at the cellular and molecular level and may ultimately lead to innovative treatments for BLB dysfunction-related hearing loss.

描述（由申请人提供）：耳蜗血管纹中的血迷路屏障（BLB）维持内耳的耳蜗电位、离子传输和液体平衡。长期以来，BLB 的破坏一直被认为是多种听力障碍的主要病因，包括自身免疫性内耳疾病、梅尼埃病、脑膜炎相关的迷路炎和几种遗传相关疾病。然而，尽管 BLB 很重要，但控制 BLB 渗透性的机制仍然很大程度上未知。我们实验室最近的一项研究意外地发现，除了内皮细胞（EC）、基底膜和周围的周细胞外，BLB 中还存在大量血管周围驻留巨噬细胞（PVM）。 PVM 通过细胞质过程（末端足）与血管紧密接触，其中含有大量囊泡和转运蛋白。我们假设 PVM 和 EC 在生理上耦合以控制血管纹中的水和离子运动。在这个项目中，我们询问 PVM 是否有助于 BLB 的完整性。如果是这样，PVM 是否通过影响紧密连接蛋白和粘附连接蛋白的表达来控制 BLB 完整性？该控制是由色素上皮衍生因子介导的吗？为了检验这一假设，我们建立了一种新的原代 EC 和 PVM 细胞共培养模型，我们将其与转基因小鼠模型结合使用。转基因小鼠编码白喉毒素受体，提供短暂消耗 PVM 的系统。在解决 PVM 对 BLB 完整性的控制方面，拟议的工作将显着增强我们在细胞和分子水平上对 BLB 的理解，并可能最终导致 BLB 功能障碍相关听力损失的创新治疗。