Regulation of renal calcium transport

肾钙转运的调节

基本信息

批准号：
8435527
负责人：
Chou-Long Huang
金额：
$ 31.52万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8435527
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 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

项目摘要

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.

描述（由申请人提供）：肾脏对于维持钙稳态至关重要。大部分在肾小球过滤的钙离子 (Ca2+) 必须通过细胞旁路和跨细胞途径被肾小管重吸收。发生在远端肾小管的跨细胞 Ca2+ 重吸收约占总重吸收的 10-20%，被认为是激素（如甲状旁腺激素）和酸碱状态调节钙稳态的主要目标。位于远端肾小管顶膜的 V5 型瞬时受体电位 (TRPV5) 通道是肾脏跨细胞 Ca2+ 重吸收的看门人。我们研究的总体长期目标是了解与肾钙转运紊乱相关的生理和疾病状态下 TRPV5 调节的分子机制。为此，我们将在当前提案中研究以下 3 个目标。目标 1 将研究 TRPV5 的 pH 和 Mg2+ 调节的机制和相互关系。目标 2 将研究甲状旁腺激素 (PTH) 调节 TRPV5 的机制。目标 3 将研究抗衰老激素 Klotho 调节 TRPV5 的分子机制。我们将结合使用互补的生化、电生理和动物方法。这些研究与肾结石直接相关，因为 Mg2+ 和碱已用于治疗肾结石疾病，并且尿 Mg2+ 和尿 pH 值的改变会影响尿 Ca2+。 PTH 是一种主要的促钙激素，但 PTH 调节肾脏 Ca2+ 重吸收的机制在很大程度上仍不清楚。 Klotho 的研究将有助于我们了解 Klotho 如何降低血清磷（长寿的重要因素）而不引起骨骼问题。尿 Ca2+ 浓度是肾结石疾病的关键决定因素。这些研究将极大地增进对 TRPV5 生物学和分子调控的理解。该提案的结果可能会加深人们对结石形成和治疗过程的理解。