C3 Glomerulopathy -- A Collaborative Study

项目摘要/摘要 C3肾小球病变(C3G)是一种侵袭性的肾小球疾病，发生在任何年龄并携带 已知肾小球疾病中发生不可逆性肾功能衰竭的风险最高。肾后复发 对于大多数患者来说，移植仍然是一个主要的医疗问题。这种悲观的前景反映了一种不完整的 对C3G潜在的病理生理学的理解，这一知识差距不仅导致我们无法 来解释目前可用的抗补体药物的有限成功，但也阻碍了 C3G新疗法的开发。 然而，家族性病例支持C3G是由初级补体失调引起的假设 我们对C3G的遗传学的理解是不完整的。充分说明……的作用 C3G中也缺乏自身抗体。最后，在大多数患者中，C3G遵循慢性、惰性 当然了。可以记录替代补体途径的激活，肾脏活检证实 肾小球内补体蛋白及其裂解产物的沉积。然而， 补体活性和临床结果之间的联系还知之甚少，这反映了 缺乏对C3G的纵向研究，集中在遗传学、自身抗体和补体活性上 与长期肾脏预后的关系。 在这项拨款中，我们建议： ·具体目标1.定义C3G的遗传驱动因素 ·具体目标2.确定和表征补体蛋白和转换酶的自身抗体 ·具体目标3.开发和验证临床上有用的疾病进展预测模型 C3G补充性因素的纵向数据驱动分析 完成这些目标将满足我们的短期目标，即更好地了解C3G 以及改善对C3G患者的护理，并为我们的长期目标奠定基础，即确定一个 治疗这种疾病的有效方法。

Project Summary/Abstract C3 glomerulopathy (C3G) is an aggressive form of glomerular disease that occurs at any age and carries the highest risk for irreversible renal failure of the known glomerular diseases. Recurrence post-renal transplant remains a major medical issue for the most patients. This dismal outlook reflects an incomplete understanding of the underlying pathophysiology of C3G, a knowledge gap that has not only led to our inability to explain the limited success of currently available anti-complement agents, but has also hindered the development of new therapies for C3G. Familial cases support the hypothesis that C3G results from primary complement dysregulation however our understanding of the genetics of C3G is incomplete. An adequate accounting for the role of autoantibodies in C3G is also lacking. Finally, in the majority of patients, C3G follows a chronic, indolent course. Activation of the alternative complement pathway can be documented, with kidney biopsies confirming the deposition of complement proteins and their cleavage products in the renal glomerulus. However, the association between complement activity and clinical outcome is poorly understood, a reflection of the absence of longitudinal studies of C3G focused on genetics, autoantibodies, and complement activity in relationship to long-term renal outcome. In this grant, we propose to: • Specific Aim 1. Define genetic drivers of C3G • Specific Aim 2. Identify and characterize autoantibodies to complement proteins and convertases • Specific Aim 3. Develop and validate clinically useful predictive models of disease progression in a longitudinal data-driven analysis of complement factors in C3G Completing these aims will meet our short-term goals, which are to provide a better understanding of C3G and to improve care for C3G patients, and provide a foundation for our long-term goal, which is to identify an effective treatment for this disease.