Hypercalciuria and Bone Quality in the Genetic Hypercalciuric Stone-Forming Rats

遗传性高钙尿结石大鼠的高钙尿症和骨质量

• 批准号: 8607180
• 负责人: DAVID A BUSHINSKY
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2016-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607180
• 关键词: Acute; Affect; Animal Model; Animals; Area; BMP2 gene; Biology; Bone Density; Bone Diseases; Bone Resorption; Calcium; Calculi; Chlorthalidone; Defect; Diet; Diet Modification; Dietary Intervention; Disease; Excretory function; Failure; Family; Fracture; Functional disorder; Generations; Genetic; Goals; Homeostasis; Human; Inbreeding; Intestines; Kidney; Kidney Calculi; Knowledge; Life; Measures; Mechanics; Nephrolithiasis; Osteogenesis; Pain; Paper; Pathogenesis; Patients; Peer Review; Productivity; Property; Publications; Rat Strains; Rattus; Recurrence; Reporting; Research; Risk; Signal Transduction; Skeleton; Snails; Source; Sprague-Dawley Rats; Stress; Testing; Thiazide Diuretics; Thick; Time; Tinea Favosa; Tissues; Urine; Vitamin D3 Receptor; Woman; Work; Writing; bone; bone quality; bone strength; bone turnover; experience; feeding; genetic strain; humerus; hypercalciuria; improved; man; men; spine bone structure; substantia spongiosa; transcription factor; urinary

DESCRIPTION (provided by applicant): Hypercalciuria and Bone Quality in the Genetic Hypercalciuric Stone-Forming Rat. The primary end point for successful treatment of patients with calcium (Ca) containing kidney stones is a decrease in the rate of stone recurrence. While this is an important goal, equally important is maintaining and improving the patient's bone mineral density (BMD) and bone quality. The majority of human kidney stone formers with Ca-containing kidney stones is hypercalciuric and often excretes more Ca than they absorb indicating a net loss of total body Ca. The source of this additional urine (U) Ca is almost certainly the skeleton. BMD is correlated inversely with UCa excretion. Many studies demonstrate that nephrolithiasis patients have a reduction in BMD and have an increased risk of fractures. To help understand the mechanism of idiopathic hypercalciuria in man, we developed an animal model of this disorder. Through >90 generations of successive inbreeding we established a strain of rats that now consistently excrete ~8-10 times as much urinary Ca as controls. As all of these rats form kidney stones, they have been termed genetic hypercalciuric stone-forming (GHS) rats. The GHS rats have a systemic abnormality in Ca homeostasis: they absorb more intestinal Ca, resorb more bone, and do not adequately reabsorb filtered Ca. The bone, kidney and intestine in the GHS rats have an increased number of vitamin D receptors (VDR) which may be regulated by a decreased level of the transcription factor Snail, suggesting potential underlying mechanism(s) for the hypercalciuria. We have recently found that the GHS rats have reduced cortical and trabecular BMD and decreased trabecular volume and thickness on an ample Ca diet. Their bones are brittle and fracture prone. The thiazide diuretic chlorthalidone increased their trabecular bone strength. The overall goal of this proposal is to study the relationship of hypercalciuria to BMD and bone quality in GHS rats. Since they have decreased BMD and bone quality, we propose to study their basic bone biology. We propose to explore the Snail, VDR, hypercalciuria, bone axis. We will then ask if dietary modifications to reduce hypercalciuria and stone formation will improve BMD and bone quality. We propose the following Specific Aims: 1. Test the hypothesis that the decreased BMD and bone quality in the GHS rats, compared to the parental Sprague-Dawley rats, is due primarily to enhanced bone resorption, and not decreased bone formation. 2. Test the hypothesis that suppression of Snail in GHS rats is due to either decreased signal(s) that up-regulate Snail (TGF2-1, BMP2) or enhanced signals that down-regulate Snail (miRs let-7 family). 3. Test the hypothesis that the reduced BMD and bone quality in the GHS rats can be improved by dietary measures directed toward reducing hypercalciuria. With these studies we hope to better understand the pathogenesis of hypercalciuria and decreased BMD. If the results from these studies are supported by studies in human hypercalciuric stone formers, they will have a substantial effect on treatment paradigms that will not only reduce recurrent stone formation but improve BMD and bone quality in hypercalciuric patients.

描述（由申请人提供）：遗传性高钙石材形成大鼠的高钙和骨质。成功治疗含有肾结石的钙（CA）患者的主要终点是石材复发率降低。尽管这是一个重要的目标，但同样重要的是维持和改善患者的骨矿物质密度（BMD）和骨质质量。大多数含有Ca的肾结石的人类肾脏石材形成器具有高钙尿素，并且通常比吸收更多的Ca表明总体净损失Ca。这种额外的尿液（u）Ca的来源几乎可以肯定是骨骼。 BMD与UCA排泄成反比。许多研究表明，肾结石病患者的BMD降低，骨折风险增加。为了帮助了解人类特发性高钙尿液的机制，我们开发了这种疾病的动物模型。通过> 90代连续的近亲繁殖，我们建立了一群大鼠，这些菌株现在始终排出约8-10倍的尿Ca是对照。当所有这些大鼠形成肾结石时，它们被称为遗传性高钙石形成（GHS）大鼠。 GHS大鼠在CA稳态中具有系统异常：它们吸收更多的肠道Ca，吸收更多的骨头，并且不能充分重新吸收过滤的CA。 GHS大鼠中的骨骼，肾脏和肠受体数量增加，可以通过转录因子蜗牛的水平降低来调节，这表明高钙尿症的潜在潜在基本机制。我们最近发现，GHS大鼠的皮质和小梁BMD降低，并且在足够的Ca饮食中减少了小梁体积和厚度。他们的骨头易碎，骨折。噻嗪类利尿氯丁酮增加了小梁骨强度。 该提案的总体目标是研究GHS大鼠中高钙尿与BMD与骨骼质量的关系。由于它们降低了BMD和骨质质量，因此我们建议研究其基本骨骼生物学。我们建议探索蜗牛，VDR，高钙尿，骨轴。然后，我们将询问饮食改造是否减少高钙尿和石材的形成将改善BMD和骨质的质量。我们提出以下具体目的：1。检验以下假设：与亲本Sprague-Dawley大鼠相比，GHS大鼠的BMD和骨质降低主要是由于增强的骨吸收，而不是骨形成降低。 2。检验以下假设：GHS大鼠中蜗牛的抑制是由于信号下调的信号下调（TGF2-1，BMP2）或增强信号的信号降低，或者是下调蜗牛（mirs let-7家族）的信号。 3。检验以下假设：通过针对减少高钙尿症的饮食措施，可以改善GHS大鼠的BMD和骨质质量。通过这些研究，我们希望更好地了解高钙尿症的发病机理和降低BMD。如果这些研究的结果得到了人类高钙化石材的研究的支持，它们将对治疗范式产生重大影响，这些范式不仅可以减少复发的石材形成，而且可以改善高钙牙科患者的BMD和骨骼质量。