ERYTHROCYTE POTASSIUM TRANSPORT AND VOLUME REGULATION

远程目标是为系统的设计提供知识库 诱导慢性受控红血球肿胀的方法 HbS纯合子个体红细胞的低阳离子通透性 相对于其他组织使提出药理作用成为可能 诱导红细胞肿胀的方法。然而，在这样的战略之前， 可以设计的，就要了解SS红血球是如何 将对增加其音量的尝试做出回应。另外，一个动物模型 人SS红细胞体积调节在发育过程中将是非常有用的 体内细胞体积操纵问题的解决方法。的确有 有证据表明人SS红细胞的渗透性肿胀导致激活 依赖于c1的K运输系统非常类似于我们 最近在兔子红细胞中观察到。这个K外排系统是 可能负责细胞体积的调节，这将是必不可少的 了解这一系统，以便优化战略，以扩大 细胞。第一个目的是比较K外流的特点(使用 86Rb作为示踪剂)在含氧人SS和兔红细胞中 将兔子作为动物模型进行评估。另一个目标是找到 不可逆地作用于肿胀刺激的钾外流的抑制剂； 抑制剂将允许我们确定系统是否真的 对细胞体积的调节是必不可少的。K的不可逆抑制物 外排也可能导致体外治疗，这将导致红色 细胞肿胀。为了鉴定催化转运蛋白 肿胀刺激的K外流，我们将产生单抗， 使用筛选程序来选择抑制K蛋白的抗体 外流。这种抗体在未来的分子水平上将非常有价值。 致力于交通系统的建设。该提案的最后一个主要目标是 开始描述成熟过程中阳离子转运的规律 网织红细胞。阳离子转运发生了非常显著的变化 在网织红细胞成熟过程中，对这些变化的了解将 在制定长期控制红色行动的战略方面至关重要 细胞体积。

The long range goal is to provide the knowledge base for the design of methods for inducing chronic, controlled swelling of red cells in individuals homozygous for Hb S. The low cation permeability of red cells relative to other tissues makes it feasible to propose pharmacologic methods for inducing red cell swelling. However, before such strategies can be designed, it will be necessary to understand how the SS red cell would respond to attempts to increase its volume. Also, an animal model of human SS red cell volume regulation would be very useful in developing approaches to the problem of in vivo cell volume manipulation. There is evidence that osmotic swelling of human SS red cells causes the activation of a C1-dependent K transport system that is very similar to one that we have recently observed in rabbit red cells. This K efflux system is probably responsible for cell volume regulation, and it will be essential to understand this system in order to optimize strategies for swelling the cells. The first aim is to compare the characteristics of K efflux (using 86Rb as tracer) in oxygenated human SS and rabbit red cells, in order to evaluate the rabbit as an animal model. Another aim is to find irreversibly acting inhibitors of the swelling-stimulated K efflux; such inhibitors will allow us to determine whether the system is really essential for cell volume regulation. Irreversible inhibitors of the K efflux could also lead to extracorporeal treatments that would cause red cell swelling. In order to identify the transport protein that catalyzes the swelling-stimulated K efflux, we will raise monoclonal antibodies, using a screening procedure to select antibodies that inhibit the K efflux. Such antibodies would be very valuable in future molecular-level work on the transport system. The last major aim of the proposal is to begin to characterize the regulation of cation transport in the maturing reticulocyte. Very significant changes in cation transport take place during reticulocyte maturation, and an understanding of these changes will be essential in the design of strategies for long-term manipulation of red cell volume.