Vascular Disease and Inflammation in Mice

描述（由申请方提供）：炎症过程的特征在于淋巴细胞的组织靶向积聚以及粘附分子、生长因子、蛋白酶和细胞因子的局部加工。这些过程起源于对感染因子和组织创伤的反应。诸如类风湿性关节炎、动脉粥样硬化、肺纤维化和克罗恩病的疾病是有害炎症的实例。了解细胞生物学中控制保护与慢性损伤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模型。 长期目标是了解肿瘤坏死因子α（TNF）受体和配体、TNF和光敏素（LTa）如何促进动脉粥样硬化。尽管研究表明TNF在动脉粥样硬化中发挥着有害作用，但我们的数据表明它的作用更加复杂，并且取决于动脉粥样硬化的阶段和相关的细胞类型。此外，我们是第一组表明LTa存在于动脉壁，LTa的丢失也影响动脉粥样硬化的进展。我们正在使用TNF配体或受体缺陷和转基因小鼠来证明这些分子如何在三个特定目标中促进动脉粥样硬化形成和动脉粥样硬化进展：（1）确定TNF在巨噬细胞胆固醇稳态中的作用，（2）确定TNF或LTa的药物抑制或诱导的基因表达是否导致动脉粥样硬化严重程度的改善，（3）确定动脉粥样硬化中来自造血区室的TNF家族成员与来自固定组织区室的TNF家族成员的相对贡献。 总之，这项工作将提供新的和详细的信息，TNF分子的相对贡献动脉粥样硬化。我们相信，在TNF领域仍然需要详细的知识，以实现开发利用TNF的抗动脉粥样硬化功能的疗法的重要目标。

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.