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Role of Biopolymers and Lipids in Kidney Stone Formation

生物聚合物和脂质在肾结石形成中的作用

基本信息

批准号：
6766962
负责人：
LAURIE B GOWER
金额：
$ 48.95万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-15 至 2006-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6766962
关键词：
atomic force microscopy bioengineering /biomedical engineering biomimetics calcification calcium crystallization intermolecular interaction lipid bilayer membrane molecular film nanotechnology nephrocalcinosis nephrolithiasis oxalates pathologic process polymers urinary bladder epithelium urinary calculi urine

项目摘要

The objective of the proposed bioengineering research partnership (BRP), located at the University of Florida, is to examine two key issues relevant to urolithiasis; 1) the effects of acidic biopolymers and lipid membranes on nucleation, growth and aggregation of calcium oxalate (CaOx) crystals in an artificial urinary environment; and 2) the injurious effects of a liquid-phase mineral precursor on tubular epithelial cells grown in culture. With regard to 1), many investigators have examined the promotory and inhibitory effects of acidic glycoproteins on crystal growth and aggregation. Our work differs in that a primary focus will be to investigate the relevance of a recently discovered polymer-induced liquid-precursor (PILP) process to pathological biomineralization. The PILP process generates non- equilibrium crystal morphologies which exhibit features similar to crystals found in kidney stones, such as for example, stratified spherulites. Mineral films and coatings are also deposited by the process, and repetitive depositions might lead to concentrically laminated structures, such as those commonly observed in composite stones. In addition, the interfacial aspects of this liquid-liquid phase separation process lead to a pronounced aggregation tendency of crystals. Lastly, we hypothesize that the presence of this cementatious mineral precursor in the urinary tract could influence the attachment and retention of crystals to renal epithelial cells; or the highly ionic precursor phase could cause cell injury or death, leading to the release of modulatory factors or membrane fragments, which could promote heterogeneous nucleation and/or aggregation of crystals. The proposed work consists of ten Specific Aims which fall under four topical areas: crystal-macromolecule, crystal- crystal, crystal-lipid, and crystal-cell interactions. The bioengineering techniques to be used include measurement of interparticle forces by Atomic Force Microscopy, measurement of long-range interactions between submicron CaOx particles and mimetic lipid membranes with an optical trap force transducer, and nucleation of crystals and PILP phase on mimetic lipid membranes using Langmuir monolayers. This 5-year project will enable us to assess the relevance of the PILP process to pathological calcification, as well as to perform a comparative analysis with the more traditional concepts pertaining to the role of lipids and acidic biopolymers in stone formation, and will contribute to the development of bioengineering techniques that are new to the field of stone research. The long-range clinical goal of this BRP is to provide a more effective means of diagnosis, treatment, and long-term prevention of renal calculi.

拟议的生物工程研究伙伴关系（BRP）的目标是研究与尿石症相关的两个关键问题；1)酸性生物聚合物和脂质膜对人工尿环境下草酸钙晶体成核、生长和聚集的影响；2)液相矿物前体对培养的小管上皮细胞的损伤作用。关于1)，许多研究者已经研究了酸性糖蛋白对晶体生长和聚集的促进和抑制作用。我们的工作的不同之处在于，主要重点将是研究最近发现的聚合物诱导的液体前体（PILP）过程与病理性生物矿化的相关性。PILP过程产生非平衡晶体形态，其表现出与肾结石晶体相似的特征，例如层状球晶。矿物薄膜和涂层也通过该过程沉积，重复沉积可能导致同心层压结构，例如在复合石头中常见的结构。此外，这种液-液分离过程的界面方面导致晶体的明显聚集倾向。最后，我们假设尿路中这种胶凝矿物前体的存在可能影响晶体对肾上皮细胞的附着和保留；或者，高离子前体相可能引起细胞损伤或死亡，导致调节因子或膜碎片的释放，从而促进晶体的非均质成核和/或聚集。提出的工作包括十个具体目标，落在四个主题领域：晶体-大分子，晶体-晶体，晶体-脂质，晶体-细胞相互作用。使用的生物工程技术包括原子力显微镜测量粒子间力，用光学陷阱力传感器测量亚微米CaOx粒子和模拟脂质膜之间的远程相互作用，以及使用Langmuir单层在模拟脂质膜上形成晶体和PILP相。这个为期5年的项目将使我们能够评估PILP过程与病理性钙化的相关性，并与更传统的关于脂质和酸性生物聚合物在结石形成中的作用的概念进行比较分析，并将有助于生物工程技术的发展，这是结石研究领域的新技术。该BRP的长期临床目标是为肾结石的诊断、治疗和长期预防提供更有效的手段。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calcium oxalate monohydrate precipitation at membrane lipid rafts.

DOI：
10.1021/ja042937w
发表时间：
2005-02
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Isa O. Benitez;D. Talham
通讯作者：
Isa O. Benitez;D. Talham

Mechanism of formation of concentrically laminated spherules: implication to Randall's plaque and stone formation.

DOI：
10.1007/s00240-008-0169-x
发表时间：
2009-02
期刊：
UROLOGICAL RESEARCH
影响因子：
0
作者：
Amos, Fairland F.;Dai, Lijun;Kumar, Rajendra;Khan, Saeed R.;Gower, Laurie B.
通讯作者：
Gower, Laurie B.

Genetic basis of renal cellular dysfunction and the formation of kidney stones.