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；这种现象在精子成熟和胆固醇反向运输等生物过程中发挥着核心作用。尽管这些脂质流出非常重要，但它们的机制在分子水平上尚不清楚。我们将表征去污剂、肽或蛋白质诱导的模型膜脂质提取，以确定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) 的脂质，表皮的顶层，主要负责皮肤的不渗透性。这种特殊的屏障与其大部分脂质形成的不寻常的结晶相有关。最近，我们发现该基质可能包含碳氢化合物纳米滴，这一假设可能会导致我们重新考虑对 SC 结构/功能的理解。我们将继续研究 SC 模型的结构和动力学，以确定形成这种独特的固/液基质所需的分子参数，并评估固/液平衡在皮肤不渗透性中的作用。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，并有可能改变透皮药物递送的屏障。*我的小组正在开发一种由单烷基化两亲物和甾醇形成的脂质体的新型平台，并展示了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。在下一个授权期内，我们建议 i) 表征关键的双层过程，例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，并可能为理解一些生物过程提供新的概念 b) 研究使用糖基两亲物制造非磷脂脂质体的可能性；糖基序通常是识别结合部分，这些脂质体可能能够靶向特定细胞，例如癌细胞，c) 卓越的不渗透性、受控刺激响应和智能表面的结合赋予这些纳米载体令人感兴趣的潜力具有挑战性的药物的脂质体递送。