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.

妊娠期间新发育高血压的抗斜力（PE）与其他器官功能障碍有关 以及慢性免疫激活，是母亲和胎儿发病率和死亡率的主要原因。 当前唯一有效的PE治疗方法是胎儿 - 抛胶单元的递送。早产交付 胎儿是胎儿生长限制（FGR）的主要原因，与较高的风险有关 心血管，代谢和神经系统疾病后期。体育女性表现出慢性免疫 通过增加T辅助细胞和B细胞的激活来激活，从而产生激动剂自身抗体 血管紧张素II型受体（AT1-AA）。在导致高血压的许多途径中暗示AT1-A A 在PE中，包括氧化应激，天然杀伤细胞活化以及对血管紧张素II的敏感性提高。我们的实验室 通过阻止AT1-AA的产生或活性，对母亲证明了有益的影响。利妥昔单抗 在临床上用于B细胞部署，已显示可降低平均动脉压（MAP），循环B细胞， 和先兆子痫大鼠模型中的AT1-AA。我们的实验室还使用了盖帽的七个氨基酸序列胡椒， “ N7AAC”，与AT1-AA的活性结合并阻止。这导致地图减少，自然杀手池 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 已治疗类风湿关节炎，多发性硬化症或非霍奇金淋巴瘤的孕妇已被治疗 在怀孕的头三个月期间或直到胎儿的妊娠中期，没有胎儿的病毒或 报告了死亡率。我们假设AT1-AA在PE中起病理作用，以引起高血压和 不仅对母亲，而且对胎儿的免疫激活以及用利妥昔单抗或 “ N7AAC”将长期改善孕产妇健康和后代健康。为了检验这一假设，怀孕的大鼠将 在使用Rituximab或“ N7AAC”治疗的情况下进行Rupp手术，并被允许进行。这 这些垃圾的后代将遵循十二个星期至一年。基于我们的初步 调查结果，我们假设B细胞耗尽或AT1-AA在怀孕的先兆坝中会改善 后代健康通过减少孕产妇和胎儿循环1-AA活动，炎症和后代血液 压力。以下具体目标将用于检验以下假设： 特定目的1：检验以下假设：怀孕期间的B细胞耗竭将改善后代存活， 生长和HTN响应妊娠期间的占地缺血。 特定目的2：检验以下假设：怀孕期间AT1-AA的给药将更糟的后代更糟 长期生存，生长和心血管健康。 特定目的3：检验以下假设：怀孕期间的“ N7AAC”治疗将改善后代生存， 生长和HTN响应妊娠期间的占地缺血。