Pro-inflammatory S100 protein as disease modifier in calcific aortic valve diseas

促炎 S100 蛋白作为钙化性主动脉瓣疾病的疾病调节剂

• 批准号: 8697130
• 负责人: Marion A Hofmann Bowman
• 金额: $ 38.71万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697130
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Atherosclerosis; Attenuated; Bacterial Artificial Chromosomes; Binding; Blood Vessels; Cardiac; Cardiovascular system; Cell Death; Cells; Cellular Stress; Chronic; Chronic Kidney Failure; Coronary; Development; Disease; Echocardiography; Evaluation; Gene Cluster; Genes; Genetically Engineered Mouse; Goals; Health; Heart; Heart Diseases; Heart Valves; Human; Hyperlipidemia; Inflammation; Inflammatory; Kidney; Kidney Diseases; Laboratories; Laboratory Research; Leukocyte L1 Antigen Complex; Lipids; Mediating; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myofibroblast; Names; Oxidative Stress; Pathology; Pathway interactions; Patients; Process; Proteins; Regulatory Element; Research; Role; S100 Proteins; S100A12 gene; S100A8 gene; S100A9 gene; Serum; Signal Transduction; Simvastatin; Staging; Stress; Surgical Valves; Testing; Therapeutic; Thioctic Acid; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Smooth Muscle; Vascular calcification; Work; abstracting; aging population; aortic valve; aortic valve disorder; calcification; cytokine; functional disability; human S100A12 protein; in vivo; interest; man; mortality; prevent; quinoline; receptor for advanced glycation endproducts; research study; response; stressor; therapeutic target; valve replacement; vascular inflammation

DESCRIPTION (provided by applicant): Calcific aortic valve disease is a growing health problem in our aging population. To overcome our limited understanding in the disease process and to develop therapeutic strategies beyond valve replacement, better animal models are critically needed. To date, most animal models have focused on hyperlipidemia-induced vascular inflammation. Our research laboratory focuses on the cytokine-like protein S100A12, which is not present in mice. The absence of S100A12 in mice could be one reason for an overall reduced amount of vascular inflammation seen in normolipidemic mice. We now developed a new humanized transgenic mouse with expression of human S100/calgranulins (S100A12, S100A8 and S100A9) in tissues that normally express these proteins by using the human S100 gene cluster with its endogenous regulatory elements. These mice are termed hBAC-S100 since a bacterial artificial chromosome was used to generate this model. These mice have a "pro-inflammatory" milieu and develop aortic valve disease with micro-calcification in a lipid neutral manner. In AIM 1 we would like to examine systemic and local inflammatory state in transgenic hBAC-S100 mice and study mechanisms by which S100/Calgranulins induce calcification of the aortic valve. In AIM 2 we would like to use the humanized S100/calgranulin mouse to develop new models of advanced calcific aortic valve disease by exposing these mice to additional vascular stressors, like hyperlipidemia and chronic kidney disease. It is our hypothesis that human S100A12 is a disease-modifying factor that accelerates calcific aortic valve disease in metabolically challenged mice by its pro-apoptotic effects on stressed cells. In our previous work we demonstrated vastly accelerated atherosclerosis and vascular calcification in transgenic mice with expression of human S100A12 targeted to the vascular smooth muscle and exposed to hyperlipidemia or chronic kidney disease. In AIM 3 we would like to test the hypothesis that limiting S100/calgranulin induced chronic inflammation by either preventing activation of its receptor RAGE or by impaired downstream signaling of the S100/RAGE axis will attenuate the progression of calcific aortic valve disease in vivo. Our research will contribute to a better understanding of the relationship of systemic and local aortic valve inflammation. Delineating the mechanisms by which S100/calgranulin regulates its effect on aortic valve remodeling will identify those steps that should be targeted for therapy. Our experiments will identify whether the S100/calgranulins/RAGE axis is a sufficient therapeutic target for aortic valve disease. (End of Abstract)

描述（由申请人提供）： 钙化性主动脉瓣疾病是我们老龄化人口中日益严重的健康问题。为了克服我们对疾病过程的有限理解，并开发瓣膜置换术以外的治疗策略，迫切需要更好的动物模型。迄今为止，大多数动物模型都集中在高血压诱导的血管炎症。我们的研究实验室专注于类精氨酸蛋白S100 A12，这是不存在于小鼠。小鼠中S100 A12的缺乏可能是在血脂正常小鼠中观察到的血管炎症的总体减少量的一个原因。我们现在开发了一种新的人源化转基因小鼠，其在正常表达这些蛋白质的组织中表达人S100/calgranulins（S100 A12、S100 A8和S100 A9），通过使用人S100基因簇及其内源性调控元件。这些小鼠被称为hBAC-S100，因为细菌人工染色体被用于产生该模型。这些小鼠具有“促炎症”环境，并以脂质中性的方式发展出伴有微钙化的主动脉瓣疾病。在AIM 1中，我们将检测转基因hBAC-S100小鼠的全身和局部炎症状态，并研究S100/Calgranulins诱导主动脉瓣钙化的机制。在AIM 2中，我们希望使用人源化S100/钙颗粒蛋白小鼠，通过将这些小鼠暴露于额外的血管应激源（如高脂血症和慢性肾病）来开发晚期钙化性主动脉瓣疾病的新模型。我们的假设是，人S100 A12是一种疾病修饰因子，通过其对应激细胞的促凋亡作用加速代谢挑战小鼠的钙化主动脉瓣疾病。在我们以前的工作中，我们证明了在转基因小鼠中，表达针对血管平滑肌的人S100 A12并暴露于高脂血症或慢性肾脏疾病，大大加速了动脉粥样硬化和血管钙化。在AIM 3中，我们想验证这样的假设，即通过阻止其受体α的激活或通过S100/β轴的下游信号传导受损来限制S100/钙颗粒蛋白诱导的慢性炎症将在体内减弱钙化性主动脉瓣疾病的进展。我们的研究将有助于更好地了解系统性和局部主动脉瓣炎症的关系。描述S100/钙颗粒蛋白调节其对主动脉瓣重塑作用的机制将确定那些应该作为治疗目标的步骤。我们的实验将确定S100/calgranulins/calcium轴是否是主动脉瓣疾病的充分治疗靶点。 (End摘要）