PFOA targets B cell lipid raft organization and function

项目总结 全氟和多氟烷基物质(PFAS)是一组合成的有机化学品，广泛用于 消费品。鉴于其化学稳定性，全氟辛烷磺酸在环境中的持久性很高，并且 在供水、食品、土壤和动植物中检测到。全氟辛烷磺酸具有免疫毒性作用。 值得注意的是，有证据表明，传统的全氟辛酸(PFOA)会损害体液。 免疫，免疫系统的手臂，驱动B细胞产生抗体。中的一个主要限制 该领域的一个问题是，全氟辛酸失调体液免疫的潜在靶点和机制尚不清楚。 因此，本应用的目的是探索新的细胞和分子机制靶点。 全氟辛酸。全氟辛酸的一个新靶点是B细胞脂筏。脂筏是血浆中紧密堆积的区域。 由鞘磷脂/磷脂和胆固醇制成的膜，作为膜蛋白的平台 以有效地传输下行信号。质膜脂筏在控制B细胞中起着关键作用 激活。因此，了解全氟辛酸是如何导致失调的B细胞脂筏形成的 为该化合物诱导免疫毒性提供了一个新的机制靶点。在此，我们建议 中心假设：全氟辛酸增加了不稳定的质膜脂筏的丰度 幼稚的B细胞。从机理上讲，这是由于全氟辛酸进入脂筏，从而驱动脂筏-- 相关的脂类进入质膜的非RAFT区域。因此，全氟辛酸创建了一个 阻碍信号受体在脂筏内的有效定位，这是有效的 幼稚B细胞的下游激活。为了检验这一假设，我们提出了两个创新性地合并的目标 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 全氟辛烷酸失调节B细胞脂筏的稳定性和丰度。目标2将确定全氟辛酸如何 调节特定受体在脂筏中的募集及其功能后果。总体而言，这一高 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点 全氟辛酸。这些研究将通过开辟一条专注于以下方面的研究新途径而产生持续的影响 了解全氟辛酸和其他全氟辛酸如何控制不同B细胞的脂筏组织和功能 人群和其他关键细胞类型的体液免疫。最终，这一系列研究将改善我们的 了解全氟辛烷磺酸如何发挥免疫毒性作用，这可以导致有针对性的干预和改进 治疗对暴露的反应。

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.