NEUROENDOCRINE ABNORMALITIES INDUCED BY SLEEP DEPRIVATIO

睡眠剥夺引起的神经内分泌异常

• 批准号: 6187935
• 负责人: CAROL A EVERSON
• 金额: $ 36.36万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187935
• 关键词: disease /disorder model; endocrine disorder; gene induction /repression; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary axis; immunocytochemistry; in situ hybridization; laboratory rat; median eminence; messenger RNA; neuroendocrine system; paraventricular nucleus; pituitary gland; pituitary thyroid axis; prolactin; receptor expression; sleep deprivation; somatotropin; thyroid hormones; thyronines; thyrotropin releasing hormone; thyroxine; triiodothyronine

DESCRIPTION (adapted from applicant's abstract): Sleep is a vital biological process necessary to maintain cognitive ability and physical health. Profound sleep disturbance/deprivation in humans is nearly always associated with disease, and sleep deprivation in patients is considered a high risk factor for mortality. In animal models of sleep deprivation, morbidity is associated with septicemia subsequent to a constellation of neuroendocrine changes, most notably hypothyroxinemia. Preliminary data have shown that neuroendocrine abnormalities extend to deficiencies in growth hormone (GH) and prolactin (PRL), and have the potential to explain most of the pathology induced by sleep deprivation. There is strong evidence that the neuroendocrine changes are centrally mediated. The following three specific aims are intended to test the main hypothesis that sleep deprivation results in hypothalamic dysfunction: Aim 1: To determine whether centrally-mediated hypothyroxinemia is due to deficient proTRH expression and TRH secretion in sleep-deprived animals. Proposed studies will determine whether TRH mRNA expression in the paraventricular nucleus and TRH content in the median eminence are suppressed and unresponsive to low T4, indicating impaired thyroid hormone regulation at the level of the hypothalamus. The pathway of T3 feedback to PVN neurons will be examined to determine the degree of up-regulation in response to low T4. Potential TRH responsiveness of thyrotrophs will be assessed by evaluating TRH receptor mRNA expression in the pituitary. Aim 2: To identify regulatory mechanisms responsible for reduced growth hormone and prolactin levels in sleep-deprived rats. Proposed studies will examine the regulation of PRL and GH in individual rats during the course of sleep deprivation by studying stimulatory and inhibitory mechanisms and response that could be responsible for the deficiency at the hypothalamic and pituitary levels. Aim 3: To delineate effects of sleep deprivation on thyroid hormone processing in the brain. Low thyroid hormone concentrations in sleep-deprived rats imply decreased T4 availability for import to the brain and ensuing centrally-mediated dysfunction common to the clinical hypothyroid state. Proposed studies will examine the content and regulation of iodothyronines in the sleep deprived brain. These studies will delineate the abnormalities in brain endocrine regulation resulting from sleep deprivation and determine the mechanisms responsible for peripheral endocrine changes that underlie its associated systemic pathologies.

描述（改编自申请人的摘要）：睡眠是一种重要的生物 维持认知能力和身体健康所必需的过程。深刻的 人类的睡眠障碍/剥夺几乎总是与 疾病，而患者睡眠不足被认为是该病的高危因素 死亡。在睡眠剥夺的动物模型中，发病率与 一系列神经内分泌变化引起的败血症，大多数 尤其是低甲状腺素血症。初步数据显示，神经内分泌 异常延伸至生长激素 (GH) 和催乳素缺乏 (PRL)，并有可能解释睡眠引起的大部分病理学 剥夺。有强有力的证据表明神经内分泌的变化 中央调解。以下三个具体目标旨在测试 睡眠剥夺导致下丘脑功能障碍的主要假设： 目标 1：确定中枢介导的低甲状腺素血症是否由以下原因引起 睡眠不足的动物中 proTRH 表达和 TRH 分泌不足。 拟议的研究将确定 TRH mRNA 表达是否在 室旁核和正中隆起的 TRH 含量受到抑制 对低 T4 没有反应，表明甲状腺激素调节受损 下丘脑的水平。 T3 反馈至 PVN 神经元的途径 进行检查以确定响应低 T4 的上调程度。 通过评估 TRH 来评估促甲状腺细胞的潜在 TRH 反应性 垂体中受体 mRNA 的表达。 目标 2：确定导致生长激素减少的调节机制 和睡眠剥夺大鼠的催乳素水平。拟议的研究将审查 睡眠过程中大鼠个体 PRL 和 GH 的调节 通过研究刺激和抑制机制以及反应来剥夺 可能是下丘脑和垂体缺乏的原因 水平。 目标 3：描述睡眠不足对甲状腺激素处理的影响 在大脑中。睡眠不足的大鼠体内甲状腺激素浓度较低意味着 输入大脑的 T4 可用性降低，从而导致 临床甲状腺功能减退状态常见的中枢介导功能障碍。 拟议的研究将检查碘甲状腺原氨酸的含量和调节 睡眠不足的大脑。 这些研究将描述大脑内分泌调节的异常 睡眠不足造成的后果，并确定造成这种情况的机制 周围内分泌变化是其相关全身病理的基础。