The Role of Interleukin-2 in Vascular Smooth Muscle Cell Homeostasis

IL-2 在血管平滑肌细胞稳态中的作用

• 批准号: 7875330
• 负责人: Lucile E Wrenshall
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-12 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875330
• 关键词: Actins; Address; Affect; Aneurysm; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biological Assay; Biology; Blood Vessels; Bypass; Carbohydrates; Cardiovascular Diseases; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Chemistry; Country; Development; Digestion; Disease; Drug Delivery Systems; Dyes; Enzymes; Exhibits; Failure; Functional disorder; Future; Generations; Goals; Heparitin Sulfate; Homeostasis; Human; Human Pathology; Hyperplasia; Immunology; Impairment; Individual; Interleukin-2; Knockout Mice; Knowledge; Label; Laboratories; Lead; Learning; Location; Lymphocyte; Maintenance; Measures; Mission; Modeling; Morphology; Mus; Oligosaccharides; Operative Surgical Procedures; Organ Transplantation; Pathologic; Pathology; Pathway interactions; Phenotype; Play; Prevalence; Prevention; Process; Proteoglycan; Public Health; Qualifying; Reagent; Regulation; Research; Role; Rupture; Shapes; Smooth Muscle Myocytes; Specimen; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; United States; Vascular Diseases; Veins; Venous; Western Blotting; Work; base; design; heparanase; human disease; human tissue; in vivo; inhibitor/antagonist; innovation; insight; mortality; novel; novel therapeutics; polysulfated glycosaminoglycan; prevent; public health relevance; response; restenosis; therapeutic development; therapy design; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Control of smooth muscle cell proliferation plays a critical role in several pathologic conditions including atherosclerosis, aneurysms, transplant vasculopathy, restenosis following endo-surgical stenting of vessels, and failure of vein grafts. Although excess vascular smooth muscle cell (VSMC) proliferation is involved in neointimal hyperplasia, and apoptosis of VSMCs is involved in aneurysm formation and atherosclerotic plaque rupture, much information has yet to be learned about how SMC proliferation is controlled in vivo and how said control fails in disease processes. This gap in knowledge impedes the development of new therapeutic or preventative measures aimed at correcting SMC dysfunction. This laboratory has recently discovered that interleukin-2 (IL-2) contributes to the maintenance of VSMCs in vivo. The overall goal of this laboratory is to understand the regulation and function of IL-2, and how impairment of either contributes to human pathology. The object of this proposal is to begin to establish the impact of IL-2 on VSMC biology. The central hypothesis is that IL-2 promotes the survival and maintenance of a differentiated phenotype in vascular smooth muscle cells. This hypothesis will be tested by the following specific aims: Aim I: Establish how monomeric and multimeric IL-2 influence VSMC function. This aim will be accomplished through testing the influence of IL-2 on several standard assays of VSMC function. Aim II: Determine whether VSMC release heparan sulfate- bound IL-2 and whether the released IL-2 influences VSMC function. This aim will be achieved through the use of a transwell assay, in which VSMC are separated from pieces of artery. Release of IL-2 will be assessed and heparanase inhibitors will be used to determine the role of this enzyme. Aim III: Establish the influence of IL-2 on aneurysm formation in vivo. This aim will be accomplished by Western blot analysis of the forms of IL- 2 present in human aneurysm tissue specimens, and by determining whether IL-2 can reverse aneurysm formation in IL-2 deficient mice. The proposed work is innovative, because it capitalizes on the novel findings that IL-2 is associated with heparan sulfate oligosaccharides present within large and small arteries and that in these location heparan sulfate-bound IL-2 influences VSMC phenotypes and survival. Completion of the proposed studies will provide an enhanced understanding of how vascular cell homeostasis is regulated via a here-to-for unknown pathway initiated by IL-2. This contribution is significant because the regulation of vascular cell homeostasis underlies a multitude of vascular pathologies, yet therapeutic interventions targeting smooth muscle cells are extremely limited. Since cardiovascular disease is the number one cause of mortality in the United States, this work addresses the NIH's mission to treat human disease. Knowledge gained from both proposed and future studies will support the establishment of new therapeutics, drug delivery systems, and even tissue constructs that target or utilizes smooth muscle cells. PUBLIC HEALTH RELEVANCE: Abnormalities in vascular smooth muscle cells underlie many pathologic conditions including atherosclerosis, aneurysms, and failure of vein grafts and transplanted organs. The proposed studies concern gaining a better understanding of how proliferation and death is regulated in vascular smooth muscle cells in both normal and disease states. The proposed research is of great significance to public health, given the prevalence of cardiovascular disease in the United States.

描述（由申请人提供）：平滑肌细胞增殖的控制在包括动脉粥样硬化、动脉瘤、移植血管病变、手术血管支架置入术后再狭窄和静脉移植失败在内的几种病理状况中起着关键作用。尽管过量的血管平滑肌细胞（VSMC）增殖与内膜增生有关，VSMC的凋亡与动脉瘤形成和动脉粥样硬化斑块破裂有关，但关于体内SMC增殖如何被控制以及这种控制在疾病过程中如何失效的信息还有待了解。这种知识上的差距阻碍了旨在纠正SMC功能障碍的新治疗或预防措施的发展。本实验室最近发现，白细胞介素-2 （IL-2）有助于维持VSMCs在体内。本实验室的总体目标是了解IL-2的调节和功能，以及两者的损伤如何导致人类病理。本提案的目的是开始建立IL-2对VSMC生物学的影响。核心假设是IL-2促进血管平滑肌细胞分化表型的存活和维持。这一假设将通过以下具体目标进行验证：目标一：确定单体和多聚体IL-2如何影响VSMC功能。这一目标将通过测试IL-2对几项VSMC功能标准测定的影响来实现。目的二：确定VSMC是否释放硫酸肝素结合的IL-2，以及释放的IL-2是否影响VSMC功能。这一目标将通过使用transwell分析来实现，其中VSMC从动脉碎片中分离出来。将评估IL-2的释放，并使用肝素酶抑制剂来确定该酶的作用。目的三：建立体内IL-2对动脉瘤形成的影响。这一目标将通过Western blot分析人类动脉瘤组织标本中存在的IL-2的形式，并确定IL-2是否可以逆转IL-2缺陷小鼠的动脉瘤形成来实现。提出的工作是创新的，因为它利用了IL-2与存在于大动脉和小动脉中的硫酸肝素寡糖相关的新发现，并且在这些位置硫酸肝素结合的IL-2影响VSMC表型和生存。这些研究的完成将有助于更好地理解血管细胞稳态是如何通过IL-2启动的一种未知途径进行调节的。这一贡献是重要的，因为血管细胞稳态的调节是多种血管病变的基础，但针对平滑肌细胞的治疗干预非常有限。由于心血管疾病是美国人死亡的头号原因，这项工作解决了NIH治疗人类疾病的使命。从已提出的和未来的研究中获得的知识将支持建立新的治疗方法、药物输送系统，甚至是靶向或利用平滑肌细胞的组织结构。