Inflammatory control of erythropoiesis in sickle disease

镰状病中红细胞生成的炎症控制

• 批准号: 6617865
• 负责人: ROBERT T MEANS
• 金额: $ 15.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617865
• 关键词: CD antigens; bone marrow; cell adhesion; cell population study; cytokine; erythropoiesis; hematopoietic stem cells; human subject; inflammation; patient oriented research; receptor expression; sickle cell anemia; thrombospondins

DESCRIPTION (provided by applicant): The anemia of chronic disease (ACD) is one of the most common hematologic syndromes encountered in clinical medicine. Over the last decade, studies have clearly established that ACD is a consequence of the cytokines which mediate the immune and inflammatory process. In contrast, sickle cell anemia is the result of a genetic defect producing a single amino acid change which alters the solubility of deoxygenated hemoglobin. Over the same period of time, it has become recognized that the clinical manifestations of the sickle syndromes result from a constellation of processes, including activation of inflammation. A heightened inflammatory state with consequent cytokine production can be demonstrated in patients with sickle cell disease. However, the unique characteristics of the sickle erythrocyte (including the persistent expression of CD36) alter the characteristics of the erythroid response to cytokines. Review of the literature suggests that CD36 persistence at high levels is unique to sickle erythrocytes, and contributes to their adhesive properties. In our preliminary data, we have demonstrated that CD36 is a positive regulator of erythropoiesis. As discussed above, the cytokine mediators of the inflammatory response produce ACD, and similar mechanisms can be implicated in sickle disease. Based on data in the literature and on our preliminary results reported below, it is hypothesized that CD36 expression protects sickle erythroid progenitors against cytokine suppression, and that those progenitors which persistently express CD36 have a selective growth advantage in the presence of inhibitory cytokines. This would result in the preferential production of CD36-expressing erythrocytes, which are then more likely to participate in intravascular adhesion. The cytokines involved in the inflammatory response would therefore enhance the frequency of vascular sickling events by increasing the frequency of potentially adherent erythrocytes. This hypothesis will be tested through the following Specific Aims: Specific Aim 1 will identify the differences in CD36 expression between progenitors from sickle cell patients and precursors, and those from controls. In Specific Aim 2, the differences in sensitivity to cytokine inhibition between sickle and control CFU-E, and the extent to which these differences can be attributed to differences in CD36 expression, will be defined. In Specific Aim 3, FA6-152will be used to characterize the response of CFU-E from sickle patients to CD36 activation, and to determine how CD36 activation alters the pattern of progenitor suppression by inhibitory cytokines, as well as the contribution of rhEPO to these processes; and Specific Aim 4 will characterize local cytokine production in the marrow of sickle cell patients, and how it relates to erythroid CD36 expression and to clinical phenotype.

描述（由申请人提供）： 慢性病贫血（ACD）是最常见的血液学之一 临床医学中遇到的综合征。在过去的十年中，研究 已经清楚地确定ACD是细胞因子的结果 调解免疫和炎症过程。相反，镰状细胞贫血 是产生单个氨基酸变化的遗传缺陷的结果 改变脱氧血红蛋白的溶解度。在同一时期 时间，已经认识到镰刀的临床表现 综合征是由一系列过程引起的，包括激活 炎。炎症状态增强，随之而来的细胞因子 可以在患有镰状细胞疾病的患者中证明生产。然而， 镰状红细胞的独特特征（包括持久性 CD36的表达）改变了对红斑反应的特征 细胞因子。文献的回顾表明CD36的持久性高 水平是镰状红细胞独有的，并有助于其粘合剂 特性。在我们的初步数据中，我们证明了CD36是一个 促红细胞生成的积极调节剂。如上所述，细胞因子 炎症反应的介体产生ACD，类似的机制可以 与镰状疾病有关。基于文献和我们的数据 下面报告的初步结果，假设CD36表达 保护镰状红细胞祖细胞免受细胞因子的抑制，然后 那些持续表达CD36的祖细胞具有选择性增长 在存在抑制性细胞因子的情况下的优势。这将导致 优先产生表达CD36的红细胞，然后是更多 可能参与血管内粘附。涉及的细胞因子 因此，炎症反应将增强血管的频率 通过增加潜在粘附的频率来恶心事件 红细胞。该假设将通过以下特定进行检验 目的：特定目标1将确定CD36表达的差异 来自镰状细胞患者和前体的祖细胞以及对照组的祖细胞。 在特定目标2中，对细胞因子抑制的敏感性差异 在镰刀和控制CFU-E之间以及这些差异的程度 可以归因于CD36表达的差异，将被定义。在 特定目标3，FA6-152将用于表征CFU-E的响应 镰状患者进行CD36激活，并确定CD36的激活方式 也会改变抑制性细胞因子抑制祖细胞的模式 作为Rhepo对这些过程的贡献；和特定的目标4将 表征镰状细胞患者骨髓中局部细胞因子的产生， 以及与红细胞CD36表达和临床表型的关系。