ENSEMBLE MODEL OF STRESS ACTH-ADRENAL AXIS

描述（由申请人提供）：基于一个实验装置， 在大鼠、绵羊、马和人类中的观察， 促肾上腺皮质-肾上腺皮质轴可以看作是一种动态的适应性反馈 由关键的大脑（下丘脑）调节中心监督的系统。后者 分泌ACTH（促肾上腺皮质激素）释放激素的间歇性爆发 (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 和脑下垂体前叶分泌物。全身ACTH浓度 通过时滞前馈驱动肾上腺皮质醇分泌 剂量反应函数血皮质醇通过抑制脑CRH/AVP的产生 快速速率敏感（微分）和时间延迟浓缩 相关（积分）反馈机制。皮质醇也抑制促皮质激素 通过差异反馈和垂体促肾上腺皮质激素合成分泌促肾上腺皮质激素， 通过积分反馈控制存储。虽然这种连接论的概念 合理地反映了在人类和动物中的可用观察结果， 整体促肾上腺皮质激素轴如何维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） 要求不得而知。开始正式确定管理 考虑到这一综合网络随时间变化的反应能力，目前的目标是： (a)框架和验证一个新的生物数学形式主义， 多值、非线性、时滞前馈-反馈组合控制 信号传导;以及（B）在人体中实施选定的介入实验 和马，以进一步阐明轴动力学。为此，我们提出四个 具体目的：（1）形成初步的生物数学结构， 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 联系24小时（昼夜）节律和超昼夜节律的机制假说 （脉动）输出;（3）评估稳态适应的机制， 急性皮质醇戒断和充盈驱动CRH/AVP和ACTH释放 （4）开始估计内源性 CRH/AVP-ACTH-皮质醇剂量反应特性在相应的人类和 动物模型 我们相信，上述临床、实验和 生物数学策略将进一步提高对复杂的理解 和动力学机制的病理生理控制的联合 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。

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.