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）：基于实验组装在老鼠，绵羊，马和人的观察中观察到压力响应性皮质性 - 肾上腺轴可被视为动态自适应反馈由关键大脑（下丘脑）监管中心监督的系统。后者分泌ACTH的情节爆发（肾上腺皮质激素激素） - 释放激素（CRH）和精氨酸加压素（AVP）。垂体静脉CRH和AVP 信号单独和共同起作用以刺激ACTH的合成，积累和垂体前腺的分泌。全身性ACTH浓度通过延时进料驱动肾上腺皮质醇分泌剂量反应函数。血质皮质醇通过抑制大脑/AVP的产生快速速率敏感（差异）和时间延迟的浓度依赖（积分）反馈机制。皮质醇还抑制皮质细胞 ACTH通过差分反馈和垂体ACTH的合成和通过积分反馈控制存储。而这个联系概念合理地反映了人类和动物中可用的观察结果合奏皮层轴如何保持有效的稳态和反应时间依赖于内部压力（疾病）和外部（环境）需求尚不清楚。开始正式化主导的关键机制该集成网络的时间不断变化的反应性，目前的目标是：（a）框架并验证新的生物学形式主义以封装多价，非线性，时置的组合进纸和反馈信号传导；（b）在人类中实施选定的介入实验和马以进一步阐明轴动力学。为此，我们摆出四个具体目的：（1）正式化初步的生物学结构体现了主要的生理连接和剂量反应界面在这个维持生命的轴内；（2）测试特定优先级临床链接24-H（昼夜节律）节奏和超级的机制的假设（脉冲）输出；（3）评估稳态适应机制 CRH/AVP和ACTH释放，由急性皮质醇戒断和补充驱动人和马；（4）开始估计内源性在相应人和相应的人和动物模型。我们认为，上述临床，实验性和生物学策略将进一步增强对复杂的理解和动态机制的结合病理生理控制 CRH/AVP-ACTH-COLTISOL分泌，因此澄清了诊断的新问题，治疗和预防与压力有关的疾病和残疾。