Contribution of T lymphocytes in the development of maternal syndrome in Dahl SS rats

T 淋巴细胞在 Dahl SS 大鼠母体综合征发生中的作用

• 批准号: 10076028
• 负责人: John H Dasinger
• 金额: $ 6.37万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076028
• 关键词: Contribution; lymphocytes; development; maternal; syndrome

PROJECT SUMMARY Contribution of T lymphocytes in the development of maternal syndrome in Dahl SS rats Preeclampsia (PE) is a pregnancy-specific disorder that is characterized by hypertension and proteinuria (maternal syndrome) developing after the 20th week of gestation. PE is the leading cause of maternal morbidity and mortality in the United States, affecting about 5% of pregnancies. Furthermore, women with preexisting hypertension or chronic kidney disease have an increased risk for developing PE. With rates of PE rising in the United States, the exact mechanism(s) responsible for the pathogenesis of the disease remain undetermined. The current hypothesis is thought to be a two-step process: 1) improper placentation and remodeling of the spiral arteries and 2) development of maternal syndrome. Current animal models require either a surgical or pharmacologic intervention to develop PE-like phenotypes; however, these models are not capable of investigating the first step in the disease process. An animal model that spontaneously develops PE is preferential to investigate the full course in the development of PE. Preliminary data demonstrate that the Dahl salt-sensitive (SS) rat is just such an animal model to help investigate mechanisms of PE since it spontaneously develops PE while remaining on a low salt (0.4% NaCl) diet. The present studies will test the general hypothesis that maternal syndrome in Dahl SS rats is an outcome of improper placentation resulting in an increased infiltration of T lymphocytes into kidney and placental tissues causing subsequent release of proinflammatory cytokines that contributes to the development hypertension and renal damage. To test this hypothesis, two specific aims are proposed. AIM 1 will first characterize the maternal syndrome phenotype in the Dahl SS rat on a low salt diet. To understand how T lymphocytes contribute to the pathogenesis, AIM 2 will explore the role of proinflammatory cytokine production due to infiltration of T lymphocytes into renal and placental tissue of Dahl SS rats. We have observed pregnancy- specific increases in blood pressure and proteinuria that are associated with increased infiltration of T lymphocytes into renal and placental tissues. This phenotype is consistent with what is observed in clinical settings, and this model provides a unique opportunity to study the whole disease process of PE. Completion of the studies in this proposal will establish a clear role for T lymphocytes in the pathogenesis of PE, and potentially uncover therapeutic targets to effectively treat PE.

项目摘要 T淋巴细胞在DAHL SS大鼠先兆子痫中产妇综合征发展的贡献 （PE）是一种以高血压和蛋白尿（母体综合征）为特征的妊娠特异性疾病 妊娠20周后发展。 PE是孕产妇发病率和死亡率的主要原因 美国，影响约5％的怀孕。此外，患有高血压或慢性的女性 肾脏疾病的发展风险增加。随着美国的PE率上升，确切的 负责该疾病发病机理的机制仍未确定。当前的假设是 被认为是一个两步的过程：1）螺旋动脉的胎盘不正确和重塑； 2） 孕产妇综合征的发展。当前的动物模型需要手术或药理 干预以开发类似PE的表型；但是，这些模型无法调查第一步 在疾病过程中。自发发展PE的动物模型优先研究完整的动物模型 PE开发的课程。初步数据表明，达尔盐敏感（SS）大鼠就是这样 一种动物模型来帮助研究PE的机制，因为它自发地发展了PE 低盐（0.4％NaCl）饮食。目前的研究将检验一般假设，即母体综合征在 DAHL SS大鼠是胎盘不当的结果，导致T淋巴细胞浸润增加 肾脏和胎盘组织，导致随后释放促炎细胞因子，这有助于 发育高血压和肾脏损害。为了检验这一假设，提出了两个具体目标。目标1 将首先表征低盐饮食中Dahl SS大鼠中母体综合征表型。了解如何 T淋巴细胞有助于发病机理，AIM 2将探索促炎性细胞因子的作用 由于T淋巴细胞浸润到DAHL SS大鼠的肾脏和胎盘组织中。我们已经观察到怀孕 - 与t的浸润增加有关的血压和蛋白尿的特异性增加 淋巴细胞进入肾脏和胎盘组织。该表型与临床中观察到的表型一致 设置，该模型为研究PE的整个疾病过程提供了独特的机会。完成 该提案中的研究将确定T淋巴细胞在PE的发病机理中的明确作用，并有可能 发现治疗靶标可有效治疗PE。