Development of a Biomimetic Lung Surfactant Replacement

0101195 Barron在目前由NSF SGER一年拨款资助的工作的继续中，PI‘s提议详细说明这种新型的结构化、序列特定的杂聚体，以开发与天然SP-B和SP-C非常接近的仿制品，这些SP-B和SP-C将是稳定的，可用于体内使用。这一与医学相关的研究项目通过展示非天然、序列特定的聚合物在生物仿生方面的有用性，为生物材料工程领域提供了广泛影响的潜力。其目的是：(1)设计、合成、层析纯化和光谱表征螺旋两亲性LS蛋白SP-B和SP-C的类肽模拟物的二级结构；(2)作为仿生脂质混合物的铺展剂，进行类肽SP模拟物的体外生物物理表征，开展脉动气泡表面测量仪和Langmuir-Wilhelmy表面天平的研究，并与含有天然花环的LS进行比较；(3)研制一种包含磷脂和SP模拟物的治疗性、仿生性LS替代品，它比动物LS更有效、生物可用、生物相容和成本效益更高；(4)与布里格姆妇女医院合作，在RDS小鼠模型中进行优化的仿生LS替代物的体内测试；以及(5)深化目前对LS蛋白质结构特征与磷脂表面膜生物物理功能之间关系的基本认识。

0101195BarronIn continuation of work that is presently funded by a one-year NSF SGER grant, the PI's propose to elaborate on this novel class of structured, sequence-specific heteropolymers to develop close mimics of natural SP-B and SP-C, that will be stable and biocompatible for in vivo use. This medically-relevant research project offers potential for broad impact on the field of biomaterials engineering, by demonstrating the usefulness of non-natural, sequence-specific polymers for biomimicry. The aims are:(1) To design, synthesize, chromatographically purify, and spectroscopically characteize the secondary strutures of peptoid mimics of helical, amphipathic LS proteins SP-B and SP-C;(2) To perform in vitro biophysical characterization of peptoid SP mimics as spreading agents for biomimetic lipid admixtures, carrying out studies on a pulsating bubble surfactometer and a Langmuir-Wilhelmy surface balance, and making comparisons to LS containing natural petpides;(3) To formulate a therapeutic, biomimetic LS replacement containing both phospholipids and SP mimics, that is effective, bioavailable, biocompatible, and more cost-effective than animal LS;(4) To carry out in vivo testing of optimized biomimetic LS replacements in a murine model of RDS, in collaboration with Brigham and Women's Hospital; and,(5) To deepen the present fundamental understanding of the relationship between LS protein structural features and biophysical functioning in phospholipid surface films.