PFOA targets B cell lipid raft organization and function

PFOA 针对 B 细胞脂筏组织和功能

• 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
• 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

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.

项目摘要 每种和多氟烷基物质（PFA）是一组合成有机化学物质，广泛用于 消费产品。鉴于它们的化学稳定性，PFA在环境中高度持久，并且是 在供水，食品，土壤和动植物中检测到。 PFA可以执行免疫毒性作用。 值得注意的是，有证据表明，遗留PFA被称为全氟辛酸（PFOA）会损害体液 免疫，是免疫系统的臂，可驱动B细胞产生抗体。在 领域是尚不清楚PFOA失调的体液免疫学失调的潜在目标和机制。 因此，此应用的目的是探索新的细胞和分子机械靶标 PFOA。 PFOA的一个新型靶标是B细胞脂质筏。脂质筏是血浆的紧密挤压区域 由鞘脂/磷脂和胆固醇制成的膜，这些膜充当膜蛋白的平台 有效传输下游信号。质膜脂质筏在控制B细胞中具有关键作用 激活。这，了解PFOA暴露如何导致B细胞脂质筏的失调将是 提供了一个新的机械目标，通过该目标，这种复合会影响免疫毒性。在此，我们提出了 中心假设是PFOA增加了不稳定质膜脂质筏的抽象 幼稚的B细胞。从机械上讲，这是由PFOA编码为脂质筏的驱动的，从而驱动脂质筏 - 相关的脂质到质膜的非垂体区域。结果，PFOA创建了一个 有效定位脂质筏中信号接收器的障碍，这是有效的 幼稚B细胞的下游激活。为了检验假设，我们提出了两个创新合并的目标 体液免疫，毒理学和膜生物化学/生物物理学领域。 AIM 1将调查如何 PFOA失调B细胞脂质筏的稳定性和抽象。 AIM 2将决定PFOA如何 将特定接收器募集到脂质筏及其功能后果中的失调。总体而言，这个高 风险/高奖励研究将建立B细胞脂质筏生物物理组织作为新的分子靶标 PFOA。这些研究将通过开放新的研究途径持续影响。 了解PFOA和其他PFAS控制脂质筏的组织以及区分B细胞的功能 人群和其他关键细胞类型的体液免疫学类型。最终，这一研究将改善我们的 了解PFA如何执行免疫毒性作用，这可以导致有针对性的干预措施并改善 响应暴露的治疗剂。