MODELING OF NA/K PUMP ACTIVITY IN CARDIAC MYOCYTES

Na/K泵是一种重要的膜蛋白，已被广泛研究 从生化、生理学、药理学和 从生物物理学上讲。Na/K泵负责维持离子梯度 穿过细胞膜。在心脏，Na/K泵也很重要 临床上用于正性变力和变时性作用 Na/K泵活性的药理或生理变化。 尽管如此，Na/K泵的详细机制仍不清楚。 这项研究的长期目标是了解Na/K泵是如何： 1)在生理上调节其活动，对心脏 糖苷和部位危险；2)从病理生理上调节(如： 缺血和充血性心力衰竭)；以及3)参与 心脏电活动和机械活动的调节。本研究 将重点介绍计算机模型的定义和使用，以 预测Na/K泵在大范围条件下的行为， 尤其是生理和临床上相关的情况。一个 这项研究的主要目标将是将生化信息 可在Na/K泵上使用，以帮助生理和生物物理 实验。这项工作将提供对Na/K的更好的理解 泵的功能和应该导致对Na/K的作用的新的见解 泵入心脏功能。这项建议将补充正在进行的研究 在本实验室中，通过将在模型中生成的数据 Na/K泵的离子和电压依赖性的实验研究 全细胞膜片钳技术测定大鼠心肌细胞膜片钳活动 肌细胞。本研究将利用这些实验结果以及 从其他实验室发表的结果，以构建一个模型 Na/K泵。这个模型将结合已知的生物化学数据 多态环酶和生理、生物物理数据 Na/K泵功能的调节与糖苷敏感性。这个 完成这一项目的具体目标将推进我们的 对Na/K泵功能的理解和对其作用的新认识 在心脏生理学方面。

The Na/K pump is an important membrane protein which has been extensively studied biochemically , physiologically, pharmacologically and biophysically. The Na/K pump is responsible for maintaining ion gradients across the cell membrane. In the heart, the Na/K pump is also important clinically for the inotropic and chronotropic actions produced by pharmacological or physiological alterations in Na/K pump activity. Despite this, the detailed mechanism of the Na/K pump is still elusive. The long range goal of this research is to understand how the Na/K pump: 1) is physiologically regulated in its activity, sensitivity to cardiac glycosides and site danger; 2) is regulate pathophysiologically (e.g. ischemia and congestive heart failure); and 3)is involved in the regulation of electrical and mechanical activity in the heart. This study will focus on the definition and utilization of a computer model to predict the behavior of the Na/K pump under a wide range of conditions, especially physiologically and clinically relevant conditions. A principle goal of this study will be to bring the biochemical information available on the Na/K pump to aid of physiological and biophysical experimentation. This work will provide a better understanding of Na/K pump function and should lead to new insights into the role of the Na/K pump in cardiac function. This proposal will complement ongoing research in this laboratory by incorporating into the model, data produced in experimental studies on the ionic and voltage dependence of Na/K pump activity as measured with the whole-cell patch-clamp technique in isolated myocytes. This study will utilize these experimental results, as well as published results from other laboratories, to construct a model of the Na/K pump. This model will incorporate the known biochemical data of a multistate cyclic enzyme and physiological and biophysical data on the regulation of Na/K pump function and glycoside sensitivity. The completion of the specific aims of this project will advance our understanding of Na/K pump function and provide new insight into its role in cardiac physiology.