Regulation of renal calcium transport

肾钙转运的调节

• 批准号: 7797778
• 负责人: Chou-Long Huang
• 金额: $ 39.63万
• 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/7797778
• 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; Hydrolysis; 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 Hormones; Pathway interactions; Phosphorus; Physiological; Polysaccharides; Potassium; Potassium Channel; Process; Protein Kinase C; Public Health; Regulation; Renal tubule structure; Research; Rotation; Serum; Sialic Acids; Side; Signal Pathway; Stretching; Structure; Surface; Time; anti aging; apical membrane; base; bone; extracellular; hormone regulation; human PTH protein; 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。大多数在肾小球过滤的钙离子（Ca 2+）必须通过细胞旁和跨细胞途径被肾小管重吸收。发生在远端肾小管中的跨细胞Ca 2+重吸收占总重吸收的约10-20%，并且被认为是通过激素（如甲状旁腺激素）和酸碱状态调节钙稳态的主要靶点。位于远端肾小管顶膜的瞬时受体电位V5（TRPV 5）通道是肾脏跨细胞钙重吸收的守门人。我们研究的总体长期目标是了解TRPV 5在与肾钙转运紊乱相关的生理和疾病状态下调节的分子机制。为此，我们将研究本提案中的以下3个目标。目的1研究TRPV 5的pH和Mg ~（2+）调节机制及其相互关系。目的2探讨甲状旁腺激素（PTH）对TRPV 5的调控机制。目的3研究抗衰老激素Klotho对TRPV 5调控的分子机制。我们将使用互补的生物化学，电生理学和动物方法的组合。这些研究与肾结石直接相关，因为Mg 2+和碱已用于治疗肾结石疾病，尿Mg 2+和尿pH值的改变影响尿Ca 2+。PTH是一种主要的促钙激素，但PTH调节肾钙重吸收的机制在很大程度上仍然是难以捉摸的。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Ca 2+浓度是肾结石疾病的关键决定因素。这些研究将极大地促进对TRPV 5生物学和分子调控的理解。该建议的结果可以提供对结石形成和治疗过程的更好的理解。 肾结石的病因有哪些？大约20%的成年人一生中至少有一次患肾结石。尿钙排泄增加是肾结石形成的主要原因。我们的研究将有助于了解为什么钙结石的形式和设计治疗这种疾病。