Maternal Microchimerism in Renal Disease

肾脏疾病中的母体微嵌合现象

• 批准号: 7140274
• 负责人: ANNE Marguerite STEVENS
• 金额: $ 17.77万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140274
• 关键词: acute renal failure; autoimmunity; cell differentiation; cell migration; cell population study; chronic renal failure; disease /disorder etiology; disease /disorder model; fluorescent in situ hybridization; genetically modified animals; green fluorescent proteins; immunocytochemistry; immunofluorescence technique; inflammation; laboratory mouse; lupus nephritis; muscle necrosis; pathologic process; placental transfer; regeneration; renal ischemia /hypoxia; tissue mosaicism

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.

描述（由申请方提供）：本提案的目的是检验母体微嵌合体参与急性和慢性肾脏疾病发病机制的假设。急性肾衰竭导致肾小管损伤和炎症，随后再生，随后恢复接近正常的肾功能。然而，即使是康复的患者也有很差的长期并发症，死亡率高，有时会出现慢性肾衰竭。最近的干细胞移植实验表明，肾损伤后，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还是有害，或者它们如何影响长期的肾功能。此外，非宿主细胞也可能来源于妊娠，当母体细胞进入胎儿和胎儿细胞进入母体时，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，具有长期后果。PI记录了肾脏以及其他自身免疫靶器官（包括肝脏、心脏、肺和胰腺）中的FMC和MMC。PI还发现母体细胞可以分化为肾小管上皮细胞。因此，在损伤后，可以募集外来干细胞以帮助组织再生。然而，它们也提供了可再生外源抗原的潜在来源，具有引发慢性炎症的潜力。本提案旨在检验MMC在肾脏疾病中发挥致病和/或再生作用的假设。在具体目标1中，我们将在两种小鼠模型（肾缺血和横纹肌溶解）中检验急性肾损伤诱导肾脏中母体细胞扩增和分化的假设。嵌合母体细胞将在损伤之前、期间和之后进行定量和表征。具体目标2将检验MMC有助于炎症性肾病（肾小球肾炎）发病机制的假设。将在BXSB狼疮小鼠疾病的不同阶段研究肾脏中的MMC。发病前母体细胞增加提示MMC的主要致病作用。疾病发作后母体细胞增加表明MMC在炎症或组织再生中的次要作用。来自该项目的数据将建立小鼠系统，以解决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衰竭治疗方法。