PATHOPHYSIOLOGY OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS

描述（由申请人提供）：丙型肝炎（HCV）是美国最常见的血液传播感染，在世界大部分地区流行。 我们和其他人以前已经表明，在人类中，慢性丙型肝炎感染的主要肾脏表现是膜增生性肾小球肾炎（MPGN）的发展，最常与冷球蛋白血症有关。 冷球蛋白是一种免疫球蛋白，在寒冷中可逆地沉淀，导致人类全身性疾病。 胸腺基质淋巴细胞生成素（TSLP），最近克隆的细胞因子，促进B细胞发育，在转基因小鼠中的过度表达导致大量的循环混合cryopulins和肾脏疾病，非常类似于人类MPGN的生产。 在这个建议中，我们寻求支持的研究，将确定白细胞的免疫球蛋白结合Fc受体（FcR）的作用，免疫复合物沉积疾病的炎症的主要介质，在这个模型和PDGF家族的生长因子介导的肾小球系膜细胞增殖的作用。 在开发了一个可重复的模型cryogenulinemia/MPGN，我们寻求开发一个主要的修改模型的具体目标1，这将允许更好地测试治疗应用在肾小球肾炎，使我们能够调节暴露的肾脏开始cryogenulinemic刺激。 我们将使用最近建立的技术，在四环素反应调控元件的控制下，启动子调节TSLP基因的表达。具体目标2将解决MPGN的全面发展需要激活特定类型的白细胞Fc受体的假设。 将使用组合的转基因和敲除小鼠测试Fc受体的功能作用。多个Fc受体缺陷株与TSLP小鼠的近亲繁殖将阐明这两种受体介导的炎症途径在该模型中的作用。 我们将测试特定的治疗干预措施（例如，这些受体的中和抗体）以中断这些炎症途径，从而有效治疗肾小球损伤。 在具体目标3中，我们将测试阻断PDGF生长因子家族的活性在改善疾病中的功效。具体目标4将检查这些干预措施对系统性冷球蛋白血症的影响。 预计这些发现将导致更好地治疗冷球蛋白血症和相关的MPGN。

DESCRIPTION (provided by applicant): Hepatitis C (HCV) is the most common blood-borne infection in the United States and is endemic in most areas of the world. We and others have previously shown that in humans, the principal renal manifestation of chronic hepatitis C infection is development of a membranoproliferative glomerulonephritis (MPGN) most often associated with cryoglobulinemia. Cryoglobulins are immunoglobulin proteins that reversibly precipitate in the cold, leading to systemic disease in humans. Overexpression of thymic stromal lymphopoietin (TSLP), a recently cloned cytokine that promotes B cell development, in transgenic mice leads to production of large amounts of circulating mixed cryoglobulins and a renal disease that closely resembles human MPGN. In this proposal, we seek support for studies that will define the role of the immunoglobulin binding Fc receptors (FcR) of leukocytes, major mediators of inflammation in immune complex deposition disease, in this model and the role of the PDGF family of growth factors that mediates glomerular mesangial cell proliferation. Having developed a reproducible model of cryoglobulinemia/MPGN, we seek to develop a major modification of the model in Specific Aim 1 that will allow better testing of therapeutic applications in glomerulonephritis by allowing us to regulate the exposure of the kidney to the initiating cryoglobulinemic stimulus. We will place the promoter regulating expression of the TSLP gene under the control of a tetracycline responsive regulatory element using recently established technologies. Specific Aim 2 will address the hypothesis that activation of specific classes of leukocyte Fc receptors are required for the full development of MPGN. The functional role of Fc receptors will be tested using combined transgenic and knockout mice. Inbreeding of multiple Fc receptor deficient strains with TSLP mice will shed light on the role of inflammatory pathways mediated by these two receptors in this model. We will test specific therapeutic interventions (e.g., neutralizing antibodies for these receptors) to interrupt these inflammatory pathways for efficacy in treating glomerular injury. In Specific Aim 3 we will test the efficacy of blocking the activity of the PDGF growth factor family in ameliorating disease. Specific Aim 4 will examine the effects of these interventions on systemic cryoglobulinemia. It is anticipated that the findings will lead to better treatments for cryoglobulinemia and associated MPGN.