Regulation of renal calcium transport

肾钙转运的调节

• 批准号: 8033788
• 负责人: Chou-Long Huang
• 金额: $ 32.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033788
• 关键词: Accounting; Acids; Adult; Aging; Alkalies; Amino Acids; Animals; Binding; Biochemical; Calcium; Calcium ion; Calculi; Caveolae; Cell membrane; Cell surface; Defect; Disaccharides; Disease; Distal; Distal convoluted renal tubule structure; Endocytosis; Excision; Excretory function; Galectin 1; Gated Ion Channel; Gatekeeping; Glycoside Hydrolases; Goals; Homeostasis; Hormones; In Vitro; Inhibitory Concentration 50; Kidney; Kidney Calculi; Life; Ligands; Longevity; Maintenance; Mediating; Membrane Glycoproteins; Molecular; Molecular Biology; Mus; N-acetyllactosamine; N-terminal; Nephrolithiasis; Neuraminidase; Parathyroid gland; Pathway interactions; Phosphorus; Physiological; Polysaccharides; Potassium; Potassium Channel; Process; Protein Kinase C; Public Health; Regulation; Renal function; Renal tubule structure; Research; Rotation; Serum; Sialic Acids; Side; Signal Pathway; Stretching; Structure; Surface; Time; anti aging; apical membrane; base; bone; extracellular; hormone regulation; improved; inhibitor/antagonist; magnesium ion; novel; public health relevance; receptor; senescence; therapy design; urinary

DESCRIPTION (provided by applicant): The kidney is critical for maintaining calcium homeostasis. Most of the calcium ion (Ca2+) filtered at the glomerulus must be reabsorbed by tubules through both paracellular and transcellular pathways. The transcellular Ca2+ reabsorption occurring in the distal renal tubules accounts for ~10-20% of total reabsorption and is believed to be the primary target for regulation of calcium homeostasis by hormones (such as parathyroid hormone) and acid-base status. Transient receptor potential type V5 (TRPV5) channel localized to the apical membrane of distal renal tubules is a gatekeeper for transcellular Ca2+ reabsorption in the kidney. The overall long- term goal of our research is to understand the molecular mechanisms of regulation of TRPV5 in physiological and diseased states associated with disturbances of renal calcium transport. To this end, we will investigate the following 3 aims in the current proposal. Aim 1 will examine the mechanism and interrelationship between pH and Mg2+ regulation of TRPV5. Aim 2 will examine the mechanism of regulation of TRPV5 by parathyroid hormone (PTH). Aim 3 will examine the molecular mechanism of Klotho, an anti-aging hormone, in the regulation of TRPV5. We will use a combination of complementary biochemical, electrophysiological, and animal approaches. These studies are directly relevant to nephrolithiasis, since Mg2+ and alkali have been used in the treatment of kidney stone disease, and alterations in urinary Mg2+ and urinary pH influence urinary Ca2+. PTH is a principal calcitropic hormone but the mechanism by which PTH regulates renal Ca2+ reabsorption remains largely elusive. The study of Klotho will shed lights on our understanding of how Klotho can lower serum phosphorus (an important factor for longevity of life) without causing bone problems. Urinary Ca2+ concontration is critical determinant of kidney stone diseases. These studies will greatly advance understanding of TRPV5 biology and molecular regulation. Results of this proposal may provide improved undestanding of the process of stone formation and of treatment. PUBLIC HEALTH RELEVANCE: Kidney stone disease is very common. About 20% of adults suffer from kidney stone disease at least once in their life time. Increase in urinary calcium excretion is a major cause for kidney stone formation. Our studies will help to understand why calcium stone forms and to design treatment for the disease.

描述（由申请人提供）：肾脏对于维持钙稳态至关重要。在肾小球上过滤的大多数钙离子（Ca2+）必须通过小管通过细胞细胞和跨细胞途径重吸收。在远端肾小管中发生的跨细胞Ca2+重吸收占总重吸收的约10-20％，被认为是通过激素（例如甲状旁腺激素）和酸碱状态调节钙稳态的主要靶标。瞬态受体电位V5（TRPV5）通道位于远端肾小管远端膜的顶膜上是肾脏跨细胞Ca2+重吸收的守门人。我们研究的总体长期目标是了解与肾脏钙转运障碍有关的生理和患病状态中TRPV5调节的分子机制。为此，我们将在当前提案中调查以下3个目标。 AIM 1将检查TRPV5的pH和MG2+调控之间的机制和相互关系。 AIM 2将检查甲状旁腺激素（PTH）对TRPV5调节的机理。 AIM 3将检查TRPV5调节中Klotho（一种抗衰老激素）的分子机制。我们将结合互补的生化，电生理和动物方法的结合。这些研究与肾石器症直接相关，因为MG2+和碱已用于治疗肾脏结石疾病，并且尿液MG2+和尿液pH的改变影响了尿Ca2+。 PTH是主要的钙钙激素，但是PTH调节肾脏Ca2+重吸收的机制在很大程度上仍然难以捉摸。 Klotho的研究将使我们对Klotho如何降低血清磷（寿命寿命的重要因素）的理解，而不会引起骨骼问题。尿Ca2+补充是肾脏疾病的关键决定因素。这些研究将大大提高对TRPV5生物学和分子调节的理解。该提案的结果可能会改善对石材形成和治疗过程的未来。 公共卫生相关性：肾脏石材疾病非常普遍。大约20％的成年人至少患有肾结石一次。尿钙排泄的增加是肾结石形成的主要原因。我们的研究将有助于理解为什么钙石的形式并为疾病设计治疗。