六磷酸肌醇激酶-1（IP6K1）及其主要产物5-IP7调控复杂多样的细胞生物学功能。我们发现IP6K1在细胞膜中高表达。敲除IP6K1显著增加细胞膜上钠钾泵（ATP1A1）的蛋白水平。此外，敲除IP6K1引起小鼠心肌肥厚。肾小管上皮细胞高表达ATP1A1是导致水钠潴留、心脏超负荷并最终引起心肌肥厚的重要原因。我们将研究：IP6K1调控ATP1A1的分子机制；验证IP6K1通过调控肾小管上皮细胞中ATP1A1的表达量来影响血压和心脏功能。此外，我们将继续研究IP6K1在心肌细胞的功能和分子机制。本课题将首次在动物、细胞及分子水平上发现IP6K1调控ATP1A1的分子机制以及首次发现IP6K1在心肌肥厚中的作用及机制，这些发现将为理解心肌肥厚的发病机制和对其治疗提供新的干预靶点。

Inositol hexakisphosphate kinase-1 (IP6K1) generates 5-diphosphoinositol pentakisphosphate (5-IP7), which is a small molecule with high energy. IP6K1 and its product 5-IP7 mediate diverse biological functions. IP6K1 and 5-IP7 may be novel targets for therapeutic purpose. We found IP6K1 is highly expressed in plasma membrane. Knocking out IPK61 substantially increases the amount of sodium-potassium ATPase alpha-1 (ATP1A1) in the cell membrane. We also found the IP6K1 knockout mice develop cardiac hypertrophy. A higher level of ATP1A1 in renal tubule cells is associated with increased amount of sodium reabsorption and blood volume, which causes extra burden of heart, thus induces cardiac hypertrophy. We propose that: knockdown IP6K1 might induce hypertension and cause cardiac hypertrophy by regulating ATP1A1 in renal tubule cells. We will study: the mechanism by which IP6K1 regulates ATP1A1; and its role in blood sodium concentration and blood pressure. We also will study the function of IP6K1 in cardiomyocytes. We will identify protein(s) that interact with IP6K1 in cardiomyocytes; and investigate whether IP6K1 regulates the structure and function of cardiomyocytes by interacting with that specific protein(s) as well as the mechanism. This study for the first time discovers the mechanism by which IP6K1 regulates ATP1A1 and for the first time demonstrates that IPK61 regulates cardiac function and may provide a novel therapeutic target.