Understanding and exploiting lipid interactions

了解和利用脂质相互作用

• 批准号: RGPIN-2018-04768
• 负责人: Lafleur, Michel
• 金额: $ 2.62万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748688
• 关键词: Understanding; exploiting; lipid; interactions

Our research program aims at characterizing the structure and the dynamics of biological materials involving lipids to understand the mechanism of key biological events, and to develop novel biomimetics. * Some peptides and some proteins can induce lipid efflux from membranes; this phenomenon plays central roles in biological processes such as sperm maturation, and reverse transport of cholesterol. Despite the prime importance of these lipid effluxes, their mechanisms are not understood at the molecular level. We will characterize detergent-, peptide- or protein-induced lipid extraction from model membranes to define the key interactions dictating the extraction of specific lipids from membranes in order to better understand these processes.* The lipids of the stratum corneum (SC), the top layer of the epidermis, are largely responsible for the skin impermeability. This exceptional barrier is linked to the unusual crystalline phase formed by a significant proportion of its lipids. Recently, we discovered that this matrix may include hydrocarbon nanodrops, an hypothesis that may lead to reconsider our understanding of the structure/function of SC. We will continue to examine the structure and the dynamics of SC models to identify the molecular parameters required for the formation of this unique solid/liquid matrix and to assess the role of the solid/liquid balance in skin impermeability. The resulting understanding of SC lipid self-assembly will contribute to maintaining a healthy skin barrier, and potentially to altering the barrier for transdermal drug delivery.* My group is developing a novel platform of liposomes formed with a monoalkylated amphiphile and a sterol, and displaying distinct properties including a very low permeability and a very good stability in harsh milieus. In the next granting period, we propose i) to characterize key bilayer processes, such as lipid flip-flop, and cholesterol oxidation; these findings will contribute to design improved nanocarriers and may provide novel concepts in understanding some biological processes b) to examine the possibility of making non phospholipid liposomes using sugar-based amphiphile; sugar motifs are often recognition binding moieties and these liposomes may be able to target specific cells, such as cancer cells, c) that the combination of the exceptional impermeability, a controlled stimulus response, and a smart surface grants an interesting potential for these nanocarriers for liposomal delivery of challenging drugs.

我们的研究计划旨在表征涉及脂质的生物材料的结构和动力学，以了解关键生物事件的机制，并开发新型仿生学。* 一些肽和一些蛋白质可以诱导脂质从膜流出;这种现象在生物过程中起着核心作用，如精子成熟和胆固醇的反向转运。尽管这些脂质流出的首要重要性，他们的机制是不理解的分子水平。我们将表征去污剂，肽或蛋白质诱导的脂质提取模型膜，以定义决定从膜中提取特定脂质的关键相互作用，以便更好地理解这些过程。角质层（SC）（表皮的顶层）的脂质在很大程度上负责皮肤的不渗透性。这种特殊的屏障与其脂质的显著比例形成的不寻常的结晶相有关。最近，我们发现，该矩阵可能包括碳氢化合物nanodrops，一个假设，可能会导致重新考虑我们的理解的结构/功能的SC。我们将继续研究的结构和SC模型的动力学，以确定所需的分子参数形成这种独特的固体/液体基质和评估的作用的固体/液体平衡在皮肤的不渗透性。由此产生的对SC脂质自组装的理解将有助于维持健康的皮肤屏障，并可能改变经皮药物递送的屏障。我的团队正在开发一种由单烷基化两亲物和甾醇形成的新型脂质体平台，并显示出独特的特性，包括非常低的渗透性和在恶劣环境中非常好的稳定性。在下一个授权期，我们建议i）表征关键的双层过程，如脂质翻转和胆固醇氧化;这些发现将有助于设计改进的纳米载体，并可能为理解某些生物过程提供新的概念B）研究使用糖基两亲物制备非磷脂脂质体的可能性;糖基序通常是识别结合部分，并且这些脂质体能够靶向特定的细胞，例如癌细胞，c）特殊的不渗透性，受控的刺激反应，并且智能表面赠款这些纳米载体用于挑战性药物的脂质体递送的有趣潜力。