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

• 批准号: 6517941
• 负责人: LAURIE B GOWER
• 金额: $ 46.56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517941
• 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

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.

位于佛罗里达大学的拟议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液环境中草酸钙（CaOx）晶体的成核、生长和聚集的影响;和2）液相矿物质前体对培养物中生长的肾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，一个主要的重点将是调查最近发现的聚合物诱导的液体前体（PILP）过程的病理生物矿化的相关性。 PILP工艺产生非平衡晶体形态，其表现出与肾结石中发现的晶体类似的特征，例如分层球晶。 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状结构，例如在复合石材中常见的那些。 此外，该液-液相分离过程的界面方面导致晶体的显著聚集趋势。 最后，我们假设，这种胶结矿物质前体在尿路中的存在可能会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会导致细胞损伤或死亡，导致调节因子或膜碎片的释放，这可能会促进晶体的异质成核和/或聚集。 拟议的工作包括10个具体目标，这些目标属于四个主题领域：晶体-大分子，晶体-晶体，晶体-脂质和晶体-细胞相互作用。 要使用的生物工程技术包括测量原子力显微镜的粒子间的力量，测量的长程之间的相互作用的亚微米CaOx颗粒和模拟脂质膜的光学陷阱力传感器，和成核的晶体和PILP相的模拟脂质膜上使用朗缪尔单层。 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，并与有关脂质和酸性生物聚合物在结石形成中的作用的更传统的概念进行比较分析，并将有助于开发生物工程技术，这是结石研究领域的新技术。 本BRP的长期临床目标是提供一种更有效的诊断、治疗和长期预防肾结石的方法。