ERα-initiated signals in the medial amygdala prevent stress-induced hypertension

内侧杏仁核中 ERα 启动的信号可预防应激性高血压

• 批准号: 8912223
• 负责人: Antentor Othrell Hinton
• 金额: $ 3.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912223
• 关键词: Affect; African American; Agonist; Amygdaloid structure; Antihypertensive Agents; Attenuated; Award; Biological Assay; Blood Pressure; Brain; Brain Part; Brain region; Cardiovascular Diseases; Cardiovascular system; Catalytic Domain; Coagulation Process; Data; Development; Disodium Salt Nitroprusside; Drug Targeting; Educational process of instructing; Emotional; Essential Hypertension; Estradiol; Estrogen Receptors; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Etiology; Event; FOS gene; Fellowship; Female; Genes; Health; Hormonal; Human; Hypertension; Hypotension; Hypothalamic structure; Individual; Intervention; Lead; Limbic System; Medial; Mediating; Medicine; Menopause; Menstrual cycle; Mus; National Research Service Awards; Neuroblastoma; Neurons; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nitrites; Parents; Pathway interactions; Patients; Phosphorylation; Postmenopause; Production; Proto-Oncogene Proteins c-akt; Psychological Stress; Pyrazoles; Rattus; Regulation; Research; Risk; Rodent; Role; Serine Phosphorylation Site; Signal Pathway; Signal Transduction; Stress; Stroke; Testing; Thromboembolism; Woman; blood pressure reduction; clinically relevant; college; genetic variant; graduate student; hypertension treatment; novel; paraventricular nucleus; pre-doctoral; prevent; relating to nervous system; response

DESCRIPTION (provided by applicant): This is an application for a Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31- Diversity) award for Antentor Othrell Hinton, Jr., a graduate student at Baylor College of Medicine. Hypertension (HTN) is the leading cause of cardiovascular disease worldwide and the number one killer in women. Interventions that treat and prevent HTN are urgently needed. Psychological stress contributes to development of HTN in humans, and these effects are mediated at least partly by neurons in the amygdala. In humans, mice and rats, neural activities in the medial amygdala (MeA) are positively associated with levels of blood pressure (BP) during stress and estrogens attenuate stress-induced c-fos expression in the MeA via estrogen receptor-α (ERα), yet the mechanisms remain unknown. Estrogen replacement therapy (ERT) lowers BP in postmenopausal women, but it also increases the risk of stroke and thromboembolism. It is the premise of this proposal that understanding specific pathways underlying the anti-hypertensive effects of estrogens may lead to novel and safer therapies for HTN. Here we hypothesize that ERα-initiated signaling pathways in MeA neurons prevent stress-induced HTN. In Aim 1, we hypothesized that ERα in the MeA mediates estrogenic effects to prevent stress-induced HTN. We generated sim1-ERα-KO mice, in which ERα is deleted mostly from MeA SIM1 neurons. Although estrogen replacement prevented stress-induced HTN in wild type ovariectomized (OVX) females, these effects were blunted in sim1-ERα-KO mice. To confirm these findings we will stereotaxically inject AAV-Cre (vs. AAV-GFP as a control) into the MeA of lox-ERα female mice. In Aim2, we found that central administration of a selective ERα agonist, propyl pyrazole triol (PPT), in female mice increased interactions of ERα and p85a (a regulatory PI3K subunit), and increased phosphorylation of AKT (a PI3K-mediated event) in the amygdala. This led us to hypothesize that PI3K in the MeA mediates estrogenic effects to prevent stress-induced HTN. To confirm these findings, we will stereotaxically inject AAV-Cre (vs. AAV-GFP as a control) into the MeA of lox-p110a female mice. In Aim 3, preliminary data suggest that central administration of PPT stimulates nitric oxide (NO) production in the amygdala via nitrate/nitrite assay. We will test if deletion of ERα i nNOS neurons (nNOS-ERα-KO mice) will blunt anti-hypertensive effects of E2 during stress and, rescue sim1-ERα-KO female mice using a NO donor. This proposal will teach us about the role of estrogens/ERα and MeA regulation in stress-induced HTN. Our studies will prove the concept that selective activation of MeA ERα can decrease BP, and therefore may identify a novel drug target for the treatment of HTN.

描述（由申请人提供）：这是一个露丝L。Kirschstein NRSA为个人博士前奖学金，以促进健康相关研究的多样性（父母F31-多样性）奖的获奖者奥瑟尔欣顿，小，贝勒医学院的研究生高血压（HTN）是全球心血管疾病的主要原因，也是女性的头号杀手。迫切需要治疗和预防HTN的干预措施。心理压力有助于人类HTN的发展，这些影响至少部分由杏仁核中的神经元介导。在人类、小鼠和大鼠中，应激时内侧杏仁核（MeA）的神经活动与血压（BP）水平呈正相关，雌激素通过雌激素受体-α（ERα）减弱应激诱导的MeA中c-fos表达，但其机制尚不清楚。雌激素替代疗法（ERT）降低绝经后妇女的血压，但也增加了中风和血栓栓塞的风险。这是这个建议的前提，了解雌激素的抗高血压作用的具体途径可能会导致新的和更安全的治疗HTN。在这里，我们假设ERα启动的信号通路在MeA神经元防止应激诱导的HTN。在目的1中，我们假设MeA中的ERα介导雌激素效应以防止应激诱导的HTN。我们产生了sim 1-ERα-KO小鼠，其中ERα主要从MeA SIM 1神经元中缺失。虽然雌激素替代治疗可以预防野生型卵巢切除（OVX）雌性动物中应激诱导的HTN，但这些作用在sim 1-ERα-KO小鼠中减弱。为了证实这些发现，我们将立体定位地将AAV-Cre（相对于作为对照的AAV-GFP）注射到lox-ERα雌性小鼠的MeA中。在Aim 2中，我们发现雌性小鼠中枢给予选择性ERα激动剂丙基吡唑三醇（PPT）增加了ERα和p85 a（一种调节性PI 3 K亚基）的相互作用，并增加了杏仁核中AKT的磷酸化（一种PI 3 K介导的事件）。这使我们假设，PI 3 K在MeA介导雌激素的作用，以防止应激诱导的HTN。为了证实这些发现，我们将立体定位地将AAV-Cre（相对于作为对照的AAV-GFP）注射到lox-p110 a雌性小鼠的MeA中。在目标3中，初步数据表明，通过硝酸盐/亚硝酸盐测定，PPT的中央给药刺激杏仁核中一氧化氮（NO）的产生。我们将测试ERα i nNOS神经元的缺失（nNOS-ERα-KO小鼠）是否会在应激期间减弱E2的抗高血压作用，并使用NO供体拯救sim 1-ERα-KO雌性小鼠。这一建议将告诉我们雌激素/ERα和MeA调节在应激诱导的HTN中的作用。我们的研究将证明选择性激活MeA ERα可以降低血压的概念，因此可能为HTN的治疗找到新的药物靶点。