NEUROENDOCRINE ABNORMALITIES INDUCED BY SLEEP DEPRIVATIO

睡眠剥夺引起的神经内分泌异常

• 批准号: 6394144
• 负责人: CAROL A EVERSON
• 金额: $ 19.29万
• 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 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394144
• 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）：睡眠是一个重要的生物学过程， 这是维持认知能力和身体健康所必需的过程。深刻 人类的睡眠障碍/剥夺几乎总是与 睡眠不足被认为是一个高风险因素， mortality.在睡眠剥夺的动物模型中， 败血症后的一系列神经内分泌变化，大多数 尤其是低甲状腺素血症。初步数据显示，神经内分泌 异常扩展到生长激素（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，神经内分泌的变化是 中枢介导的以下三个具体目标旨在检验 睡眠剥夺导致下丘脑功能障碍的主要假设： 目的1：确定中枢介导的低甲状腺素血症是否是由于 缺乏proTRH表达和TRH分泌在睡眠剥夺的动物。 拟议的研究将确定TRH mRNA表达是否在 室旁核和正中隆起TRH含量受到抑制 对低T4无反应，表明甲状腺激素调节受损， 下丘脑的水平。T3反馈到PVN神经元的通路将 检查以确定响应于低T4的上调程度。 促甲状腺激素细胞的潜在TRH反应性将通过评估TRH 受体mRNA在垂体的表达。 目的2：确定负责生长激素减少的调节机制 和催乳素水平。拟议的研究将审查 大鼠睡眠过程中PRL和GH的调节 剥夺通过研究刺激和抑制机制和反应， 可能是下丘脑和脑垂体功能缺失的原因 程度. 目的3：描述睡眠剥夺对甲状腺激素加工的影响 在大脑中。睡眠剥夺大鼠甲状腺激素浓度低意味着 输入大脑的T4可用性降低， 临床甲状腺功能减退状态常见的中枢介导的功能障碍。 拟议的研究将检查碘甲腺原氨酸的含量和调节， 睡眠不足的大脑。 这些研究将揭示大脑内分泌调节的异常 睡眠剥夺的结果，并确定负责的机制， 外周内分泌变化是其相关全身性病理的基础。