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ENSEMBLE MODEL OF STRESS ACTH-ADRENAL AXIS

应激肾上腺轴的整体模型

基本信息

批准号：
6832787
负责人：
JOHANNES D VELDHUIS
金额：
$ 37.6万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2006-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Based on an assembly of experimental observations in the rat, sheep, horse and human, the stress-responsive corticotropic-adrenal axis can be viewed as a dynamically adaptive feedback system supervised by key brain (hypothalamic) regulatory centers. The latter secrete episodic bursts of ACTH (adrenocorticotropic hormone)-releasing hormone (CRH) and arginine vasopressin (AVP). Hypophyseal-portal venous CRH and AVP signals act individually and jointly to stimulate ACTH synthesis, accumulation and secretion by the anterior pituitary gland. Systemic ACTH concentrations in turn drive adrenal cortisol secretion via a time-lagged feedforward dose-response function. Blood cortisol inhibits brain CRH/AVP production via both rapid rate-sensitive (differential) and time-delayed concentration dependent (integral) feedback mechanisms. Cortisol also represses corticotrope ACTH secretion via differential feedback and pituitary ACTH synthesis and storage via integral feedback control. While this connectionistic concept reasonably reflects available observations in the human and animal, precisely how the ensemble corticotropic axis maintains effectual homeostasis and reacts time-dependently to internal stress (disease) and external (environmental) demands is not known. To begin to formalize the key mechanisms that govern the time-evolving reactivity of this integrated network, the present goal is to: (a) frame and validate a new biomathematical formalism to encapsulate multivalent, nonlinear, time-lagged combined feedforward and feedback signaling; and (b) implement selected interventional experiments in the human and horse to further elucidate axis dynamics. To this end, we pose four specific aims: (1) to formalize a preliminary biomathematical construct that embodies the major physiological connections and dose-response interfaces within this life-supporting axis; (2) to test specific a priority clinical hypotheses of mechanisms linking 24-h (circadian) rhythmicity and ultradian (pulsatile) output; (3) to evaluate the mechanisms of homeostatic adaptation of CRH/AVP and ACTH release driven by acute cortisol withdrawal and repletion in the human and horse; and (4) to begin to estimate endogenous CRH/AVP-ACTH-cortisol dose-response properties in corresponding human and animal models. We believe that the foregoing unique marriage of clinical, experimental and biomathematical strategies will further enhance understanding of the complex and dynamic mechanisms underlying pathophysiological control of conjoint CRH/AVP-ACTH-cortisol secretion, and thus clarify new issues in the diagnosis, treatment and prevention of stress-related disease and disability.

描述（由申请人提供）：基于一组实验对大鼠、绵羊、马和人类的观察显示，应激反应促肾上腺皮质轴可以被视为动态自适应反馈系统由主要大脑（下丘脑）调节中心监督。后者分泌阵发性 ACTH（促肾上腺皮质激素）释放激素 (CRH) 和精氨酸加压素 (AVP)。垂体-门静脉 CRH 和 AVP 信号单独或联合作用刺激 ACTH 合成、积累和垂体前叶的分泌。全身 ACTH 浓度通过时滞前馈反过来驱动肾上腺皮质醇分泌剂量反应函数。血液皮质醇通过抑制大脑 CRH/AVP 的产生快速速率敏感（差异）和延时浓度依赖（整体）反馈机制。皮质醇也会抑制促肾上腺皮质激素通过差异反馈和垂体 ACTH 合成来分泌 ACTH 通过积分反馈控制进行存储。虽然这个联结主义概念合理地反映了人类和动物的现有观察结果，准确地整体促肾上腺皮质轴如何维持有效的稳态并做出反应与时间相关的内部压力（疾病）和外部（环境）要求未知。开始规范管理的关键机制该集成网络随时间演化的反应性，目前的目标是： (a) 构建并验证新的生物数学形式主义以封装多价、非线性、时滞组合前馈和反馈信号发送； (b) 在人体中实施选定的介入实验和马进一步阐明轴动力学。为此，我们提出四点具体目标：（1）形式化初步的生物数学构造，体现了主要的生理联系和剂量反应界面在这个生命支持轴内； (2) 测试特定的优先临床 24 小时（昼夜节律）节律与超昼夜节律联系机制的假设（脉动）输出； (3) 评价稳态适应机制由急性皮质醇撤退和补充驱动的 CRH/AVP 和 ACTH 释放人和马； (4) 开始估计内生性相应人类和动物体内的 CRH/AVP-ACTH-皮质醇剂量反应特性动物模型。我们相信，上述临床、实验和临床的独特结合生物数学策略将进一步增强对复杂问题的理解联合病理生理控制的动态机制 CRH/AVP-ACTH-皮质醇分泌，从而阐明诊断中的新问题，治疗和预防与压力有关的疾病和残疾。