Vascular Disease and Inflammation in Mice

描述(由申请人提供)：炎症过程的特征是淋巴细胞在组织中的靶向聚集，以及黏附分子、生长因子、蛋白酶和细胞因子的局部形成。这些过程起源于对感染性病原体和组织创伤的反应。类风湿性关节炎、动脉粥样硬化、肺纤维化和克罗恩病等疾病都是有害炎症的例子。了解控制保护与慢性损伤的细胞生物学中的关键关系，对于预防疾病和治疗数百万患有此类疾病的人至关重要。在这里，我们研究动脉粥样硬化作为炎症的模型。 长期目标是了解肿瘤坏死因子受体及其配体、肿瘤坏死因子和淋巴毒素(LTA)在动脉粥样硬化中的作用。尽管研究表明，肿瘤坏死因子在动脉粥样硬化中起着有害的作用，但我们的数据表明，它的作用更为复杂，而且依赖于动脉粥样硬化的阶段和所涉及的细胞类型。此外，我们是第一个发现LTA存在于动脉壁的小组，LTA的缺失也影响动脉粥样硬化的进展。我们正在使用缺乏和转基因的肿瘤坏死因子配体或受体来展示这些分子如何在三个特定目标中促进动脉粥样硬化的形成和动脉粥样硬化的进展：(1)确定肿瘤坏死因子在巨噬细胞中胆固醇稳态中的作用，(2)确定药物抑制或诱导肿瘤坏死因子或LTA的基因表达是否导致动脉粥样硬化的严重程度的改善，(3)确定来自造血室的肿瘤坏死因子家族成员相对于固定的组织室在动脉粥样硬化中的相对贡献。 总体而言，这项工作将提供关于肿瘤坏死因子分子对动脉粥样硬化的相对贡献的新的和详细的信息。我们认为，在肿瘤坏死因子领域仍需要详细的知识，以实现开发利用肿瘤坏死因子抗动脉粥样硬化功能的治疗这一重要目标。

DESCRIPTION (provided by applicant): Inflammatory processes are characterized by tissue- targeted accumulations of lymphocytes and the local elaboration of adhesion molecules, growth factors, proteases and cytokines. These processes originate in response to infectious agents and tissue trauma. Diseases such as rheumatoid arthritis, atherosclerosis, pulmonary fibrosis and Crohn's disease are examples of deleterious inflammation. Understanding the pivotal relationships in cell biology which control protection versus chronic damage is critical for preventing disease and treating millions of individuals with such diseases. Here, we study atherosclerosis as a model for inflammation. The long range goal is to understand how tumor necrosis factor alpha (TNF) receptors and ligands, TNF and lymphotoxin (LTa) contribute to atherosclerosis. Although studies implicate TNF as playing a deleterious role in atherosclerosis, our data suggests that its contribution is more complicated and dependent upon stage of atherosclerosis and cell types involved. In addition, we are the first group to show that LTa is present at the artery wall and loss of LTa also influences the progression of atherosclerosis. We are using mice deficient and transgenic in TNF ligands or receptors to demonstrate how these molecules contribute to atherogenesis and atheroprogression in three specific aims: (1) determine the role of TNF in cholesterol homeostasis in macrophages, (2) determine whether pharmaceutical inhibition or induced gene expression of TNF or LTa results in improvement in atherosclerosis severity, (3) determine the relative contribution of TNF family members derived from the hematopoietic compartment versus the fixed tissue compartment in atherosclerosis. Overall, this work will provide new and detailed information about the relative contributions of TNF molecules to atherosclerosis. We believe that detailed knowledge is still needed in the TNF field to realize the important goal of developing therapies which harness anti-atherogenic functions of TNF.