Maternal Microchimerism in Renal Disease

描述(申请人提供)：这项建议的目的是测试母体微嵌合体参与急性和慢性肾脏疾病发病机制的假设。急性肾功能衰竭导致肾小管损伤和炎症，继而再生，随后肾功能恢复接近正常。然而，即使康复的患者的长期预后也很差，死亡率很高，有时还会出现慢性肾功能衰竭。最近的干细胞移植实验表明，在肾脏损伤后，干细胞迁移到肾脏，并分化为肾小管上皮细胞和内皮细胞。然而，目前尚不清楚肾脏中的新细胞是有益的还是有害的，也不清楚它们如何影响长期的肾功能。此外，非宿主细胞也可能来自妊娠，当母体细胞进入胎儿，胎儿细胞进入母体，导致持续的胎儿和母体微嵌合体(FMC，MMC)。因此，FMC和/或MMC也可能参与肾损伤和/或再生，产生长期后果。PI记录了肾脏中的FMC和MMC，以及自身免疫的其他靶器官，包括肝、心、肺和胰腺。PI还发现母细胞可以分化为肾小管上皮细胞。因此，在损伤后，可能会招募外来干细胞来帮助组织再生。然而，它们也提供了一种潜在的可再生外来抗原来源，有可能引发慢性炎症。这项建议旨在验证MMC在肾脏疾病中起致病和/或再生作用的假设。在具体目标1中，我们将在肾缺血和横纹肌溶解两种模型上检验急性肾损伤诱导肾脏母细胞扩张和分化的假说。嵌合的母体细胞将在损伤之前、期间和之后进行量化和表征。特定目标2将检验MMC在一种炎症性肾脏疾病--肾小球肾炎的发病机制中的作用这一假设。BXSB狼疮小鼠肾脏中的MMC将在疾病的不同阶段进行研究。母体细胞在发病前增加可能是MMC的主要致病因素。疾病发作后母体细胞的增加表明MMC在炎症或组织再生中起次要作用。来自该项目的数据将建立小鼠系统，在其中研究母体细胞在肾脏中的作用机制，以及开发和测试基于母体细胞的急性肾功能衰竭治疗方法。

DESCRIPTION (provided by applicant): The objective of this proposal is to test the hypothesis that maternal microchimerism is involved in the pathogenesis of acute and chronic renal disease. Acute renal failure leads to tubular injury and inflammation followed by regeneration with subsequent recovery of near normal renal function. However, even recovered patients have poor long-term prognoses, with high mortality and sometimes chronic renal failure. Recent experiments in stem cell transplantation suggest that after renal injury stem cells migrate to the kidney and differentiate into tubular epithelial and endothelial cells. It is not clear, however, whether the new cells in the kidney are helpful or harmful, or how they affect long-term renal function. Moreover, non-host cells may also be derived from pregnancy, when maternal cells pass into the fetus and fetal cells into the mother, leading to persistent fetal and maternal microchimerism (FMC, MMC). Thus, FMC and/or MMC could also participate in renal injury and/or regeneration, with long-term consequences. The PI has documented FMC and MMC in the kidney, as well as other target organs of autoimmunity, including liver, heart, lung, and pancreas. The PI has also discovered that maternal cells can differentiate into renal tubular epithelial cells. Thus after injury foreign stem cells may be recruited to aid in tissue regeneration. However, they also provide a potential source of renewable foreign antigen with the potential to trigger chronic inflammation. This proposal aims to test the hypothesis that MMC plays a pathogenic and/or regenerative role in renal disease. In Specific Aim 1 we will test the hypothesis that acute renal injury induces the expansion and differentiation of maternal cells in the kidney in two mouse models, renal ischemia and rhabdomyolysis. Chimeric maternal cells will be quantified and characterized before, during and after injury. Specific Aim 2 will test the hypothesis that MMC contributes to the pathogenesis of an inflammatory renal disease, glomerulonephritis. MMC in the kidney will be studied at different stages of disease in the BXSB lupus mouse. Maternal cells increased prior to onset of disease would suggest a primary pathogenic role for MMC. Maternal cells increased after disease onset would suggest a secondary role for MMC in inflammation or tissue regeneration. The data derived from this project will establish mouse systems in which to address mechanisms of maternal cell action in the kidney, as well as to develop and test treatments for acute renal failure based on maternal cells.