The Role of AT1-AA in Causing Adult Hypertension in Offspring Born with FGR

AT1-AA 在 FGR 后代引起成人高血压中的作用

• 批准号: 10759366
• 负责人: Nathan E. Campbell
• 金额: $ 3.17万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2025-09-13
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759366
• 关键词: Address; Adult; Affect; Angiotensin II; Antihypertensive Agents; Attenuated; Autoantibodies; B-Cell Activation; B-Lymphocytes; Binding; Birth; Blood Pressure; Blood Vessels; Blood coagulation; CD4 Positive T Lymphocytes; Cell secretion; Cerebrum; Child; Chronic; Circulation; Clinical; Disease; Fetal Development; Fetal Growth Retardation; Fetal Mortality Statistics; Fetus; First Pregnancy Trimester; Frequencies; Functional disorder; Future; Glucocorticoids; Growth; Health; Helper-Inducer T-Lymphocyte; Hypertension; Impaired cognition; Incidence; Inflammation; Inflammatory; Invaded; Ischemia; Kidney; Laboratories; Life; Magnesium Sulfate; Maternal Health; Maternal Mortality; Metabolic; Metabolic Diseases; Mississippi; Modeling; Monoclonal Antibody CD20; Morbidity - disease rate; Mothers; Multiple Sclerosis; NK Cell Activation; Non-Hodgkin' s Lymphoma; Operative Surgical Procedures; Organ; Outcome; Oxidative Stress; Pathologic; Pathway interactions; Peptide Initiation Factors; Perfusion; Play; Postpartum Period; Pre-Clinical Model; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant Women; Premature Birth; Production; Proteinuria; Rattus; Receptor, Angiotensin, Type 1; Reporting; Rheumatoid Arthritis; Risk; Role; Seizures; Spasm; Spiral Artery of the Endometrium; Stroke; T-Lymphocyte; Testing; Umbilical Cord Blood; United States; Uterus; Woman; anti-CD20; blood pressure elevation; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; cell type; comorbidity; cytokine; effective therapy; endothelial dysfunction; fetal; immune activation; immune function; improved; male; mitochondrial dysfunction; mortality; myometrium; nervous system disorder; novel therapeutics; offspring; pathophysiology of preeclampsia; pregnant; pressure; protein aminoacid sequence; response; rituximab; standard of care; therapeutic evaluation; trophoblast

Preeclampsia (PE), new-onset hypertension during pregnancy, is associated with other organ dysfunction as well as chronic immune activation and is the leading cause of morbidity and mortality for the mother and fetus. The only currently effective treatment for PE is the delivery of the fetal-placental unit. Preterm delivery of the fetus is the primary cause of fetal growth restriction (FGR) and is associated with an elevated risk for cardiovascular, metabolic, and neurological disorders later in life. PE women demonstrate chronic immune activation through increased activation of T helper cells and B cells producing an agonistic autoantibody to the angiotensin II type I receptor (AT1-AA). AT1-A A is implicated in numerous pathways contributing to hypertension in PE including oxidative stress, natural killer cell activation, and increased sensitivity to angiotensin II. Our lab has demonstrated beneficial effects for the mother by blocking the production or activity of AT1-AA. Rituximab used clinically for B cell depletion, has been shown to decrease mean arterial pressure (MAP), circulating B cells, and AT1-AA in a rat model of preeclampsia. Our lab has also used a capped seven amino acid sequence peptide, ‘n7AAc’, to bind to and block the activity of AT1-AA. This has resulted in decreased MAP, natural killer cell activation, and oxidative stress in a rat model of preeclampsia. While ‘n7AAc’ has not been used clinically, pregnant women with rheumatoid arthritis, multiple sclerosis, or non-Hodgkin’s lymphoma have been treated with Rituximab during or up to the first trimester of their pregnancies with no elevation in fetal morbidities or mortalities reported. We hypothesize that AT1-AA plays a pathologic role in PE to cause hypertension and immune activation not only for the mother but also for the fetus and that maternal treatment with Rituximab or ‘n7AAc’ will improve maternal health and offspring health long-term. To test this hypothesis, pregnant rats will undergo the RUPP surgery with or without treatment with Rituximab or ‘n7AAc’ and be allowed to deliver. The offspring from these litters will be followed for a period of twelve weeks to one year. Based on our preliminary findings, we hypothesize that B cell depletion or AT1-AA blockade in pregnant preeclamptic dams will improve offspring health by reducing maternal and fetal circulating AT1-AA activity, inflammation, and offspring blood pressure. The following specific aims will be used to test this hypothesis: Specific Aim 1: To test the hypothesis that B cell depletion during pregnancy will improve offspring survival, growth, and HTN in response to placental ischemia during pregnancy. Specific Aim 2: To test the hypothesis that administration of AT1-AA during pregnancy will worsen offspring survival, growth, and cardiovascular health long-term. Specific Aim 3: To test the hypothesis that ‘n7AAc’ treatment during pregnancy will improve offspring survival, growth, and HTN in response to placental ischemia during pregnancy.

子痫前期(PE)是妊娠期新发的高血压，与其他器官功能障碍有关，如 以及慢性免疫激活，是导致母亲和胎儿发病和死亡的主要原因。 目前对PE唯一有效的治疗方法是胎儿-胎盘单元的分娩。早产 胎儿是胎儿生长受限(FGR)的主要原因，并与 晚年的心血管、代谢和神经疾病。体育女性表现出慢性免疫力 通过增加T辅助细胞和B细胞的激活来激活，产生激动型自身抗体 血管紧张素II I型受体(AT1-AA)。AT1-A A与多种导致高血压的途径有关 在PE中包括氧化应激、自然杀伤细胞激活和对血管紧张素II的敏感性增加。我们的实验室 通过阻断AT1-AA的产生或活性而对母亲产生有益的影响。利妥昔单抗 临床上用于B细胞耗尽，已被证明能降低平均动脉压(MAP)，循环中的B细胞， 和AT1-AA在先兆子痫大鼠模型中的表达。我们实验室还使用了一个封顶的七个氨基酸序列多肽， ‘n7AAc’，与AT1-AA结合并阻断其活性。这导致MAP减少，自然杀伤细胞 先兆子痫大鼠模型中的激活和氧化应激。虽然‘n7AAc’尚未在临床上使用， 患有类风湿性关节炎、多发性硬化症或非霍奇金淋巴瘤的孕妇已接受治疗 在怀孕前三个月或怀孕前三个月服用利妥昔单抗，胎儿发病率或 据报道死亡人数。我们假设AT1-AA在PE中起病理作用，导致高血压和 免疫激活不仅对母亲，而且对胎儿和孕妇使用利妥昔单抗或 ‘n7AAc’将长期改善母子健康。为了验证这一假设，怀孕的大鼠将 接受RUPP手术，无论是否使用Rituximab或‘n7AAc’治疗，并允许分娩。这个 这些幼崽的后代将被跟踪12周至一年。根据我们的初步调查 结果，我们假设妊娠期先兆子痫母细胞B细胞耗竭或AT1-AA阻断将得到改善 通过减少母体和胎儿循环AT1-AA活性、炎症和子代血液来实现子代健康 压力。以下具体目标将被用来检验这一假设： 具体目标1：为了验证怀孕期间B细胞耗尽将提高后代存活率的假设， 妊娠期胎盘缺血对生长和HTN的影响。 具体目标2：检验怀孕期间服用AT1-AA会使后代恶化的假设 长期的生存、成长和心血管健康。 具体目标3：为了验证怀孕期间进行n7AAc治疗将提高后代存活率的假设， 妊娠期胎盘缺血对生长和HTN的影响。