RESPIRATORY AND AUTONOMIC MECHANISMS POTENTIALLY UNDERLYING SIDS

呼吸和自主机制可能是小岛屿发展中国家的基础

• 批准号: 8282985
• 负责人: EUGENE Edward NATTIE
• 金额: $ 58.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8282985
• 关键词: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acute; Affect; Age; Air; Anatomy; Animal Model; Animals; Apnea; Baroreflex; Binding; Body Temperature; Brain Stem; Breathing; Carrier Proteins; Cell physiology; Cells; Chronic; Citalopram; Controlled Study; Data; Development; Early Diagnosis; Elements; Etiology; GABA Receptor; Gender; Genetic; Heart Rate; Hour; Human; Hypercapnia; Hypoxia; Infant; Injection of therapeutic agent; Knockout Mice; Larynx; Lesion; Life; Measurement; Measures; Mus; Neurons; Pharmacological Treatment; Physiology; Pregnancy; Preparation; Rattus; Reflex action; Risk; Risk Factors; Rodent; Role; Serotonin; Serotonin Receptor 5-HT1A; Shipping; Ships; Sleep; Substance P; Substance P Receptor; Sudden infant death syndrome; System; Temperature; Testing; Time; Toxin; Transgenic Mice; Wakefulness; base; cigarette smoking; cisterna magna; gabazine; gamma-Aminobutyric Acid; human data; infancy; maternal cigarette smoking; neurochemistry; postnatal; pregnant; pup; receptor; receptor binding; recombinase; research study; respiratory; response; stressor; substance P-saporin; warm temperature

We will study the interaction among 1) a brainstem vulnerability, 2) critical age, and 2) homeostatic stressors; three factors that form the Triple Risk Hypothesis for the causation of SIDS. We will evaluate the control of breathing, heart rate and reflex apnea in developing rodents of both genders. Our brainstem vulnerabilities are chosen based on human infant data implicating abnormalities in the medullary serotonergic (5-HT) system, GABA receptor binding, and neurokinin-1 receptor (NK1R) binding, in SIDS (Introductory Overview). The use of rodents allows focus on developmental age, as in 20 postnatal days they mimic late gestation and infancy in humans, as well as genetic and pharmacological manipulation of brainstem vulerabilities. Our additional stressors, chronic intermittent hypoxia, maternal smoke exposure and warm temperatures, are epidemiologically defined risk factors for SIDS. The emphasis is on the interaction of vulnerabilities, age and stressors. Specific aim (SA) 1 focuses on 5-HT in genetically manipulated mice with reduced function of the 5-HT transport protein and with 'silenced' 5-HT neurons, i.e., a reduced ability to secrete 5-HT (produced in Project 5). SA 2 focuses on 5-HT but in developing rat pups treated by daily injections of agents to inhibit the 5-HT transport protein or block or stimulate the 5-HT1A receptor, which directly affects function of the 5- HT neuron. Binding for both the 5-HT1A receptor and the 5-HT transport protein is reduced in SIDS brainstems. SA 3 examines the role of the NK1R in developing rat pups via lesions produced by an NK1Rspecific toxin at postnatal day 4 (P4). SAs 4 and 5 will evaluate chronic intermittent hypoxia and maternal smoking, respectively, together with a brainstem vulnerability found most efficacious in SAs 1-3. In each aim, the pups will be tested at P5, P15 and P25 before and after injection of a GABA receptor blocker. We study the control of breathing and heart rate as they are strikingly variable in chance recordings from SIDS cases and inhibitory reflexes, e.g., the laryngeal chemoreflex that induces apnea when receptors around the larynx are stimulated, as they are likely contributors to SIDS. Warm temperatures-thought important in SIDSprolong this apnea and blockade of GABA receptors-abnormal in SIDS-shortens it. Our results, derived from an animal model that directly tests the Triple Risk Hypothesis, will help pinpoint possible mechanisms for SIDS and provide information of use in early detection.

我们将研究1）脑干脆弱性，2）关键年龄和2）稳态压力的相互作用； 构成了SID因子的三个风险假设的三个因素。我们将评估控制 呼吸，心率和反射呼吸暂停在发展两种性别的啮齿动物中。我们的脑干脆弱性 根据人类婴儿数据选择，该数据涉及髓质血清素能中异常（5-HT） SIDS（入门概述）中的系统，GABA受体结合和Neurokinin-1受体（NK1R）结合。 啮齿动物的使用允许专注于发育年龄，就像在出生后的20天一样，它们模仿妊娠期 人类的婴儿期以及脑干脆弱性的遗传和药理操纵。我们的 其他压力源，慢性间歇性缺氧，母体烟雾暴露和温暖的温度是 SIDS的流行病学定义的危险因素。重点是脆弱性，年龄和年龄的相互作用 压力源。特定目标（SA）1专注于遗传操纵小鼠的5-HT，其功能降低 5-HT转运蛋白和“沉默” 5-HT神经元，即分泌5-HT的能力（在 项目5）。 SA 2专注于5-HT，但在每天注射药物治疗以抑制的大鼠幼崽上 5-HT转运蛋白或阻滞或刺激5-HT1A受体，这直接影响5-的功能 HT神经元。在SIDS中，5-HT1A受体和5-HT转运蛋白的结合均降低 脑干。 SA 3检查了NK1R通过NK1RSpific产生的病变开发大鼠幼崽的作用 产后第4天（P4）的毒素。 SAS 4和5将评估慢性间歇性缺氧和母亲 在SAS 1-3中，吸烟分别与脑干脆弱性一起发现。在每个目标中， 在注射GABA受体阻滞剂之前和之后，将在P5，P15和P25下测试幼崽。我们学习 呼吸和心率的控制在SIDS案例中的机会记录中存在明显变化 和抑制反射，例如，当喉头周围的受体诱导呼吸暂停的喉化学反射 受到刺激，因为它们可能是小溪的贡献者。温暖的温度 - 在壁icsprolong中很重要 SIDS中的GABA受体呼吸暂停和封锁。我们的结果来自 直接检验三重风险假设的动物模型将有助于查明可能的机制 SIDS并提供早期检测中使用的信息。