Lung Surfactant Pathologies: Study of the Formation of Biomolecular Aggregates

肺表面活性剂病理学：生物分子聚集体形成的研究

• 批准号: 7284010
• 负责人: GUSTAVO E LOPEZ-QUINONES
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284010
• 关键词: Acute Lung Injury; Affect; Air; Alveolar; Amino Acid Sequence; Amino Acids; Arts; Cereals; Charge; Cholesterol; Code; Communities; Computational Technique; Computer Simulation; Computer software; Condition; Coupled; Degenerative Disorder; Development; Disease; Environment; Equilibrium; Infant; Ionic Strengths; Lipids; Lipoidosis; Literature; Mechanics; Methods; Modeling; Modification; Molecular; Monitor; Mutation; Neonatal Mortality; Newborn Respiratory Distress Syndrome; Pathology; Peptide Sequence Determination; Phosphatidyl glycerol; Phosphatidylglycerols; Property; Proteins; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants; Research; Sampling; Solutions; Standards of Weights and Measures; Structure; Surface; Surface Tension; System; Techniques; Temperature; Thermodynamics; Water; alveolar lamellar body; base; molecular dynamics; monolayer; novel strategies; programs; protein aggregate; protein aggregation; research study; simulation; surfactant

Pulmonary surfactant is a surface active material composed of a lipids/protein mixture that forms layered structures, i.e. Langmuir monolayer at the alveolar air/water interface and bilayers in lamellar bodies. The typical compositions of pulmonary surfactant are 50% of dipalmitolphosphotidylcholine (DPPC), 25% unsaturated phosphotidylcholine, 12% of the negatively charged phosphatidylglycerol (PG), and 8% of surfactant proteins. The remaining 5% includes other type of lipids and cholesterol. Various pathological conditions have been associated with abnormal composition levels of pulmonary surfactants. For example, an insufficient amount of pulmonary surfactants in premature or newly born infants causes respiratory distress syndrome, which is a major cause of neonatal mortality. Large quantities of certain surfactant proteins have been associated to the formation of amyloidal fibrils causing a condition termed pulmonary alveolar proteinosis (PAP). Also, inappropriate concentration of lipids in the lung surfactant can induce lipid aggregation, causing degenerative diseases such as acute lung injury and lipidosis. The detailed molecular mechanism for the aggregation of the various components of lung surfactant is not fully understood. We hypothesize that aggregation of surfactant proteins and/or lipids will occur at certain lipid layered-structure and thermodynamic states (composition, temperature and surface tension). The main reason for our hypothesis is that intermolecular forces in the lipidic-layered environment can promote the necessary structural changes in proteins, and hence the formation of aggregates. We also hypothesize that general rules can be derived allowing us to make predictions regarding the formation of aggregates in lung surfactants. To investigate our hypotheses, we propose to use state-of-the-art computer simulations. Specifically, coarse-grained, united, and all-atom interparticle potentials will be used and/or developed that permit an accurate description of the forces acting on the systems being investigated. Computational techniques such as Monte Carlo and Molecular Dynamics, coupled to efficient sampling techniques, will be used to determine the properties and conditions for the formation of aggregates in pulmonary surfactants. The research will permit the elucidation of the mechanism of formation of lipid/protein aggregates in lung surfactants and the correlation of this formation to pathologies. This correlation will help to the development of new approaches for the treatment of PAP and lipidosis, as well as other protein aggregation related diseases.

肺表面活性物质是一种表面活性物质，由脂质/蛋白质混合物组成， 结构，即肺泡气/水界面处的朗缪尔单层和板层体中的双层。的 肺表面活性剂的典型组合物是50%的二棕榈醇磷脂酰胆碱（DPPC）、25%的二棕榈醇磷脂酰胆碱（DPPC）和25%的二棕榈醇磷脂酰胆碱（DPPC）。 不饱和磷脂酰胆碱、12%的带负电荷的磷脂酰甘油（PG）和8%的 表面活性剂蛋白。剩下的5%包括其他类型的脂质和胆固醇。各种病理 这些病症与肺表面活性剂的异常组成水平有关。比如说， 早产儿或新生儿的肺表面活性剂量不足， 窘迫综合症，这是新生儿死亡的主要原因。大量的某些表面活性剂 蛋白质与淀粉样纤维的形成有关， 肺泡蛋白沉积症（PAP）。此外，肺表面活性物质中脂质浓度不当可诱导脂质 聚集，引起退行性疾病，如急性肺损伤和肺水肿。详细的分子 肺表面活性物质的各种组分聚集的机制还没有完全理解。我们 假设表面活性剂蛋白质和/或脂质聚集将发生在某些脂质层状结构上 和热力学状态（组成、温度和表面张力）。我们的主要原因是 假设是，在脂质层环境中的分子间力可以促进必要的 蛋白质的结构变化，从而形成聚集体。我们还假设， 可以推导出允许我们对肺中聚集体的形成进行预测的规则 表面活性剂为了研究我们的假设，我们建议使用最先进的计算机模拟。 具体地，将使用和/或开发粗粒、联合和全原子粒子间势， 可以准确描述作用在被研究系统上的力。计算 蒙特卡罗和分子动力学等技术，再加上高效的采样技术，将 用于确定肺表面活性剂中聚集体形成的性质和条件。 该研究将有助于阐明肺内脂质/蛋白质聚集体形成的机制 表面活性剂以及这种形成与病理学的相关性。这种关联将有助于发展 治疗PAP和纤维化的新方法，以及其他与蛋白质聚集相关的新方法。 疾病