ENSEMBLE MODEL OF STRESS ACTH-ADRENAL AXIS

描述(由申请人提供)：基于一组实验性的 在大鼠、绵羊、马和人身上观察应激反应 肾上腺皮质轴可被视为动态适应性反馈 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 信号单独和共同作用刺激ACTH的合成、积累 以及脑下垂体前叶的分泌。全身性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(差动)和延时浓缩 依赖(整体)反馈机制。皮质醇也抑制促肾上腺皮质激素 ACTH的差异反馈分泌和垂体ACTH的合成 通过积分反馈控制进行存储。虽然这种连接主义的概念 合理地反映了在人类和动物中的可用观察，准确地 整体皮质轴如何维持有效的动态平衡和反应 对内部压力(疾病)和外部压力(环境)具有时间依赖性 需求是未知的。开始正规化管理 该集成网络的反应性随时间演变，目前的目标是： (A)构建并验证一种新的生物数学形式，以封装 多值、非线性、时滞组合前馈和反馈 信号；以及(B)在人体内实施选定的介入性实验 和马来进一步阐明轴的动力学。为此，我们摆出四个姿势 具体目标：(1)形成一个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 在这个维持生命的轴线内；(2)测试特定的优先临床 24小时(昼夜节律)节律性与超常节律机制的假说 (3)评价动态平衡适应的机制。 急性皮质醇戒断和耗竭引起的CRH/AVP和ACTH释放 人和马；(4)开始估计内生性 CRH/AVP-ACTH-皮质醇的剂量-反应特性 动物模型。 我们相信，上述临床、实验和实验的独特结合 生物数学策略将进一步加强对该复合体的理解 和联合的病理生理控制的动力学机制 CRH/AVP-ACTH-皮质醇分泌，从而阐明诊断中的新问题， 治疗和预防与压力相关的疾病和残疾。

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.