CALCIUM ION TRANSPORT ATPASE AND ALTERED CALCIUM ION HOMEOSTASIS

细胞内钙在许多细胞过程中起着基础性作用。 包括增殖、分化和肌肉收缩/关系。 他 肌浆/内质网钙转运ATPase(SERCAs)是关键 参与胞质和胞内钙调节的酶 CA2_STORES。SERCA表达和/或功能可能发生改变 在某些生理或病理生理条件下，包括 高血压和心力衰竭。SERCA泵的特定抑制剂是 越来越多地被用于研究：(1)细胞内钙稳态，(2) SERCA基因表达的调控；(3)结构-功能 SERCA内部的关系。我们开发了一种新型的基于 在这些SERCA泵抑制剂上，这构成了目前 申请。特别是，在各种选择下，我们发展了 策略，对该抑制剂具有高度抗性的哺乳动物细胞系 特异性SERCA泵阻滞剂thapsigargin(TG)和2，5- 二叔丁基-1，4对苯二酚(DBHQ)。这导致了某些 细胞内钙离子的生化和功能适应 耐药细胞系中的动态平衡和SERCA泵。在这 应用，我们提出了一系列详细的分子生物学研究。 SERCA泵存在于耐药细胞系中，以解剖 它们内部可能发生的关于以下方面的适应范围 在这种特定的选择压力下的表达和功能。这些 研究将产生关于控制机制的新信息 改变(和潜在的病理性)钙稳态，这是相关的 对了解与异常相关的疾病状态很重要 在钙动态平衡中。

Intracellular Ca2+ plays a fundamental role in many cellular processes including proliferation, differentiation, and muscle contraction/relation. he sarcoplasmic/endoplasmic reticulum Ca2+ transport ATPase (SERCAs) are key enzymes involved in the regulation of cytoplasmic Ca2+ and intracellular Ca2_ stores. Alterations in SERCA expression and/or function can occur under certain physiological or pathophysiological conditions including hypertension and heart failure. Specific inhibitors of the SERCA pump are increasingly being used to study: (1) intracellular Ca2+ homeostasis, (2) regulation of SERCA gene expression, and (3) structure-function relationships within SERCA. We have developed a novel model system based on these SERCA pump inhibitors, which forms the basis for the current application. In particular, we have developed, under various selection strategies, mammalian cell lines that are highly resistant to the inhibitor effects of the specific SERCA pump blockers thapsigargin (TG) and 2,5- di(tert-butyl)-1, 4 hydroquinone (DBHQ). This results in certain biochemical and functional adaptations with respect to cellular Ca2+ homeostasis and SERCA pumps in the resistant cell lines. In this application, we propose a series of detailed molecular biological studies o the SERCA pumps present in the resistant cell lines in order to dissect the potential range of adaptations that can occur within them with respect to expression and function under such specific selective pressure. These studies will yield novel information regarding mechanisms controlling altered (and potentially pathologic) Ca2+ homeostasis, which are relevant and important to understanding disease states associated with abnormalities in Ca2+ homeostasis.