PFOA targets B cell lipid raft organization and function

PFOA 针对 B 细胞脂筏组织和功能

基本信息

批准号：
10665277
负责人：
SAAME R SHAIKH
金额：
$ 42.54万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-12 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665277
关键词：
Address Animals Antibody Formation Antigens Automobile Driving B-Cell Activation B-Lymphocytes Biochemical Biochemistry Biological Assay Biomimetics Biophysics CD80 Antigens Cell membrane Cell surface Cells Cholesterol Data Environment Exposure to Female Food Humoral Immunities Immune system Impairment Intervention Ligand Binding Link Lipids Membrane Membrane Microdomains Membrane Proteins Mission Modeling Molecular Molecular Target Mus NMR Spectroscopy Organic Chemicals Phospholipids Plants Poly-fluoroalkyl substances Population Quantitative Microscopy Receptor Signaling Research Role Signal Transduction Soil Sphingolipids Testing Therapeutic Thermodynamics Toxicology Up-Regulation Viscosity Water Supply amphiphilicity arm cell type cellular targeting chemical stability consumer product cytokine drinking water experimental study high reward high risk imaging approach immunotoxicity improved in vivo evaluation innovation insight male novel perfluorooctanoic acid prevent receptor recruit response transmission process

项目摘要

PROJECT SUMMARY Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals that are widely used in consumer products. Given their chemical stability, PFAS are highly persistent in the environment and are detected in the water supply, food products, soil, and plants/animals. PFAS can exert immunotoxic effects. Notably, there is evidence that the legacy PFAS known as perfluorooctanoic acid (PFOA) can impair humoral immunity, the arm of the immune system that drives antibody production from B cells. A major limitation in the field is that underlying targets and mechanisms by which PFOA dysregulates humoral immunity are unknown. Therefore, the objective of this application is to explore new cellular and molecular mechanistic targets of PFOA. One novel target of PFOA is B cell lipid rafts. Lipid rafts are tightly packed regions of the plasma membrane made of sphingolipids/phospholipids and cholesterol that serve as platforms for membrane proteins to efficiently transmit downstream signals. Plasma membrane lipid rafts have a critical role in controlling B cell activation. Thus, understanding how PFOA exposure leads to dysregulated B cell lipid raft formation would provide a new mechanistic target by which this compound induces immunotoxicity. Herein, we propose the central hypothesis that PFOA increases the abundance of unstable plasma membrane lipid rafts of naïve B cells. Mechanistically, this is driven by PFOA incorporating into lipid rafts and thereby driving lipid raft- associated lipids into non-raft regions of the plasma membrane. As a consequence, PFOA creates an impediment toward effective localization of signaling receptors within lipid rafts, which is required for efficient downstream activation of naïve B cells. To test the hypothesis, we propose two aims that innovatively merge the fields of humoral immunity, toxicology, and membrane biochemistry/biophysics. Aim 1 will investigate how PFOA dysregulates the stability and abundance of B cell lipid rafts. Aim 2 will determine how PFOA dysregulates recruitment of specific receptors into lipid rafts and its functional consequences. Overall, this high risk/high reward study will establish B cell lipid raft biophysical organization as a new molecular target of PFOA. These studies will have a sustained impact by opening a new avenue of research focused on understanding how PFOA and other PFAS control lipid raft organization and function of differing B cell populations and other key cell types of humoral immunity. Ultimately, this line of research will improve our understanding of how PFAS exert immunotoxic effects, which can lead to targeted interventions and improved therapeutics in response to exposure.

项目概要全氟烷基物质和多氟烷基物质 (PFAS) 是一组广泛用于鉴于其化学稳定性，PFAS 在环境中具有高度持久性，并且在供水、食品、土壤和植物/动物中检测到的 PFAS 可以产生免疫毒性作用。值得注意的是，有证据表明，被称为全氟辛酸 (PFOA) 的传统 PFAS 会损害体液免疫，驱动 B 细胞产生抗体的免疫系统的一个主要限制。目前，PFOA 调节体液免疫的潜在目标和机制尚不清楚。因此，本应用的目的是探索新的细胞和分子机制靶点 PFOA 的一个新靶标是 B 细胞筏脂质。脂筏是血浆中紧密堆积的区域。由鞘脂/磷脂和胆固醇制成的膜，作为膜蛋白的平台质膜脂筏在控制 B 细胞中发挥着关键作用。因此，了解 PFOA 暴露如何导致 B 细胞脂筏形成失调。提供了该化合物诱导免疫毒性的新机制靶标。中心假设是 PFOA 增加了不稳定质膜脂筏的丰度从机制上讲，这是由 PFOA 掺入脂筏并驱动脂筏驱动的。相关脂质区域进入质膜的非筏，因此，PFOA 产生了一个阻碍脂筏内信号受体有效定位，这是有效脂筏所必需的为了检验这一假设，我们提出了两个创新性合并的目标。体液免疫、毒理学和膜生物化学/生物物理学领域将研究如何进行。 PFOA 失调 B 细胞筏脂质的稳定性和丰度目标 2 将如何确定 PFOA。总体而言，这种高水平会调节脂筏中特定受体的募集及其功能后果。风险/高回报研究将建立 B 细胞脂筏生物物理组织作为新的分子靶标这些研究将开辟一条新的研究途径，产生持续的影响。了解 PFOA 和其他 PFAS 如何控制不同 B 细胞的脂筏组织和功能最终，这一系列研究将改善我们的体液免疫。了解 PFAS 如何发挥免疫毒性作用，这可以导致有针对性的干预措施并改善对暴露做出反应的治疗方法。