HEREDITARY AND ACQUIRED PROTEIN S DEFICIENCY

遗传性和后天性蛋白质缺乏症

• 批准号: 3341456
• 负责人: PHILIP Cinnamon COMP
• 金额: $ 9.09万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-06-01 至 1991-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3341456
• 关键词: anticoagulants; blood coagulation disorders; blood coagulation tests; blood proteins; clotting factor; complement; complement inhibitors; complement pathway; congenital blood protein disorder; disseminated intravascular coagulation; human subject; immunoelectrophoresis; immunohematology; nephrotic syndrome; nutrition related tag; protein C; systemic lupus erythematosus; thromboembolism; thrombosis; vitamin K

Protein S is a cofactor for the anticoagulant effects of activated protein C. We have discovered that individuals who lack functional protein S activity are prone to thromboembolic disease, presumably due to an inability to regulate blood clotting. However, while these individuals lack functional protein S activity, protein S antigenic levels are normal or mildly reduced. All or most of their protein S is complexed with C4-binding protein, an inhibitor of the complement system, and is not functionally active. In normals only 60% of the total protein S is complexed to C4-binding protein. We wish to determine why this shift in protein S distribution occurs in the familial functional protein S deficiency. To accomplish this goal, we will investigate the possible causes for the shift in the following order: First, initial determinations indicate that C4-binding protein is elevated in the functionally deficient individuals and we will determine if the levels of C4-binding protein in the patients' plasma are sufficient to explain the shift by mass action. This will require well-validated assays for C4-binding protein levels in plasma. Secondly, we find that activation of complement in vitro results in a shift from free protein S to bound. We will determine if complement activation is also involved in the in vivo changes observed in the patients and if the observed shift is mediated through binding of C4b to C4-binding protein. If complement activation does not prove responsible for the changes in protein S states observed in patients, we will isolate patient protein S and C4-binding and characterize these proteins both kinetically and structurally to determine if an abnormality in one of these proteins is responsible for the altered protein S distribution. We find that an acquired functional deficiency occurs in two major medical conditions which have thromboembolic complications - systemic lupus erythematosis and the nephrotic syndrome. Again, the protein S is shifted to the bound and inactive form. We will determine the mechanism(s) by which this shift occurs. We will investigate other medical conditions known to have thromboembolic complications to determine if acquired protein S deficiency occurs. These patient studies are the first step in the pursuit of our long-term goal which is the determination of whether or not monitoring protein S status may serve as a rational way of deciding which patients will benefit most from phrophylactic measures to prevent thromboembolic complications.

蛋白质S是活化蛋白抗凝作用的辅助因子 C.我们发现缺乏功能性蛋白质的个体 活动容易患血栓栓塞疾病，大概是由于 无法调节血液凝结。 但是，这些人 缺乏功能性蛋白质的活性，蛋白质的抗原水平正常 或轻度减少。 它们的全部或大部分蛋白质与 C4结合蛋白，补体系统的抑制剂，不是 功能活动。 在正常中，总蛋白质的60％为 复合到C4结合蛋白。 我们希望确定为什么这种转变 蛋白质的分布发生在家族功能蛋白S中 不足。 为了实现这一目标，我们将研究 按以下顺序转移：首先，初始确定表明 在功能不足的个体中，C4结合蛋白升高 我们将确定患者的C4结合蛋白水平是否水平 血浆足以解释质量作用的转移。 这会 需要对血浆中C4结合蛋白水平进行验证的测定。 其次，我们发现体外补体的激活导致转移 从自由蛋白S到结合。 我们将确定是否补充激活 还参与了患者观察到的体内变化，以及 观察到的移位是通过C4B与C4结合蛋白的结合来介导的。 如果补充激活没有证明对变化负责 在患者中观察到的蛋白质状态，我们将分离患者蛋白S 以及C4结合并表征这些蛋白质，并在动力学上和 结构上确定这些蛋白质之一的异常是否是 负责改变蛋白质的分布。 我们发现在两个主要的医疗中发生了获得的功能缺陷 有血栓栓塞并发症的疾病 - 全身性狼疮 红斑病和肾病综合征。 同样，蛋白质S移动 以绑定和非活动形式。 我们将通过 发生这种转变。 我们将调查其他医疗状况 已知有血栓栓塞并发症，以确定是否获得了蛋白质 S缺乏发生。 这些患者研究是 追求我们的长期目标，这是确定是否 监测蛋白质的状态可能是决定哪种 患者将受益于嗜噬细胞措施，以防止 血栓栓塞并发症。