PATHOPHYSIOLOGY OF CRYOGLOBULNEMIC GLOMERULONEPHRITIS

描述(申请人提供)：丙型肝炎(丙型肝炎)是美国最常见的血液传播感染，在世界上大多数地区都是地方病。我们和其他人之前已经证明，在人类中，慢性丙型肝炎感染的主要肾脏表现是发生膜增生性肾小球肾炎(MPGN)，最常与冷球蛋白血症相关。 冷冻球蛋白是一种免疫球蛋白，在寒冷中可逆沉淀，导致人类全身疾病。胸腺基质淋巴生成素(TSLP)是一种新近克隆的促进B细胞发育的细胞因子，在转基因小鼠中过表达会导致大量循环中的混合冷球蛋白的产生，并导致一种与人类MPGN非常相似的肾脏疾病。在这项提案中，我们寻求支持将确定白细胞免疫球蛋白结合Fc受体(FCR)在该模型中的作用，以及PDGF家族生长因子家族在介导肾小球系膜细胞增殖中的作用。 在开发了一个可复制的冷球蛋白血症/MPGN模型后，我们寻求在特定目标1中对该模型进行重大修改，使我们能够通过允许我们调节肾脏对启动的冷球蛋白血症刺激的暴露，更好地测试肾小球肾炎的治疗应用。我们将利用最近建立的技术，将调控TSLP基因表达的启动子置于四环素反应调控元件的控制之下。具体目标2将解决以下假设，即MPGN的充分发展需要激活特定类别的白细胞Fc受体。Fc受体的功能作用将用转基因和基因敲除小鼠相结合的方式进行测试。将多个Fc受体缺陷株与TSLP小鼠近亲交配，将有助于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)，以阻断这些炎症途径，以达到治疗肾小球损伤的效果。在具体目标3中，我们将测试阻断PDGF生长因子家族活性在改善疾病中的效果。具体目标4将检查这些干预措施对全身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.