Glycolipid biointerface to decipher disease-implicated ganglioside-protein interactions

糖脂生物界面破译疾病相关神经节苷脂-蛋白质相互作用

• 批准号: 10737003
• 负责人: QUAN JASON CHENG
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737003
• 关键词: Affinity; Anabolism; Binding; Biochemical; Biological; Biomimetics; Biophysics; Blood Cells; Bypass; Carbohydrates; Cell Adhesion; Cell Communication; Cell membrane; Cell physiology; Cells; Complex; Development; Diabetes Mellitus; Disease; EGF gene; Environment; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Family; Gangliosides; Glycocalyx; Glycolipids; Glycoproteins; Glycosphingolipids; Goals; Head; Human body; Immune; Individual; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Investigation; KDR gene; Killer Cells; Libraries; Link; Lipid Bilayers; Lipids; Malignant Neoplasms; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Modeling; Molecular; Nerve Regeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pattern; Play; Polysaccharides; Property; Proteins; Research; Role; Series; Sialic Acids; Sialyltransferases; Signal Pathway; Signal Transduction; Spectrum Analysis; Structure; Structure-Activity Relationship; Surface; Surface Plasmon Resonance; System; Techniques; Therapeutic; Toxic effect; Variant; Vascular Endothelial Growth Factors; anti-cancer; anti-cancer therapeutic; caveolin 1; glycosyltransferase; neuroregulation; new technology; novel; protein function; receptor; technology platform; therapeutic target; tumor; tumor progression

Glycolipid biointerface to decipher disease-implicated ganglioside-protein interactions All cells in the human body, including neurons, immune cells, epithelial cells, and blood cells, are coated with a dense layer of glycoproteins and glycolipids known as the glycocalyx. The extraordinary complexity in structural organization and biosynthesis of the glycocalyx has made it very difficult to comprehend the precise roles it plays in various cellular processes and thus limited its potential as therapeutic target. An important family of molecules of the glycocalyx is gangliosides, which participate in a wide array of intercellular events such as modulating killer cell toxicity, controlling neural regeneration, and promoting cell adhesion during inflammation. Gangliosides are found to play important roles in altering and mediating affinity properties of the membrane proteins in certain cancers, and are clearly implicated in insulin-resistant type 2 diabetes. However, the biochemical mechanisms of gangliosides’ effect on tumor and type 2 diabetes appear to be extremely complex, and a major portion of ganglioside pathology remains elusive. Lack of suitable techniques is a main obstacle that has principally limited the research on gangliosides and restricted our ability to understand their roles on protein function. We propose to build a highly effective, glyco-diverse, biomimetic membrane interface system and a new bioanalytical platform to study the ganglioside-protein interactions implicated in several diseases at the molecular level. A ganglioside library will be created for construction of interface mimics with precisely controlled glycan moiety, composition and packing biophysics as observed in those disease states. The proposed approach bypasses complex endogenous synthesis of gangliosides, and creates a novel hosting environment with programmed tuning in ganglioside makeups for elucidating structure- function relationships with the membrane proteins. The effect of gangliosides on protein interactions will be primarily investigated by surface plasmon resonance (SPR) spectroscopy, which quantifies molecular binding and affinity changes under systematically varied composition and headgroup moiety (Aim 1). We will then study and understand the inhibitory/promoting function of gangliosides on proteins EGFR and VEGFR, angiogenic activators linked to progression of cancer (Aim 2), and on interactions of insulin, insulin receptor and caveolin-1 (Aim 3), a key system implicated in insulin-resistant type 2 diabetes.

糖脂生物界面用于解释疾病相关的神经节苷脂-蛋白质相互作用 人体内的所有细胞，包括神经元、免疫细胞、上皮细胞和血细胞， 被称为糖萼的糖蛋白和糖脂的致密层包覆。的非凡 糖萼的结构组织和生物合成的复杂性使得很难 理解它在各种细胞过程中发挥的确切作用，从而限制了它的潜力， 治疗靶点糖萼的一个重要分子家族是神经节苷脂，其参与 在广泛的细胞间事件如调节杀伤细胞毒性，控制神经再生， 以及在炎症期间促进细胞粘附。神经节苷脂被发现在 在某些癌症中改变和介导膜蛋白的亲和特性， 与胰岛素抵抗的2型糖尿病有关。然而，神经节苷脂的生化机制， 对肿瘤和2型糖尿病作用似乎极其复杂，且神经节苷脂的主要部分 病理学仍然难以捉摸。缺乏适当的技术是一个主要障碍， 神经节苷脂的研究，限制了我们理解它们对蛋白质功能的作用。 我们建议建立一个高效的，糖多样性，仿生膜界面系统， 一种新的生物分析平台，用于研究与多种疾病有关的神经节苷脂-蛋白质相互作用 在分子水平上。将创建一个神经节苷脂库，用于构建界面模拟物 在这些疾病中观察到的精确控制的聚糖部分、组成和包装生物物理学 states.所提出的方法绕过了神经节苷脂的复杂内源性合成， 一种新颖的托管环境，可编程调整神经节苷脂组成，以阐明结构- 与膜蛋白的功能关系。神经节苷脂对蛋白质相互作用的影响将 主要通过表面等离子体共振（SPR）光谱来研究，其量化分子 在系统变化的组成和头基部分下的结合和亲和力变化（目的1）。我们 然后将研究和了解神经节苷脂对蛋白EGFR的抑制/促进功能， VEGFR，与癌症进展相关的血管生成激活剂（Aim 2），以及胰岛素的相互作用， 胰岛素受体和小窝蛋白-1（Aim 3），一个与胰岛素抵抗2型糖尿病有关的关键系统。