PFOA targets B cell lipid raft organization and function

项目摘要 全氟烷基和多氟烷基物质（PFAS）是一组合成有机化学品，广泛用于 消费品。鉴于其化学稳定性，PFAS在环境中具有高度持久性， 在供水、食品、土壤和植物/动物中检测到。PFAS具有免疫毒性作用。 值得注意的是，有证据表明，被称为全氟辛酸（PFOA）的传统PFAS可以损害体液免疫功能。 免疫力，免疫系统的手臂，驱动抗体生产从B细胞。一个主要的限制， PFOA引起体液免疫失调的潜在靶点和机制尚不清楚。 因此，本申请的目的是探索新的细胞和分子机制靶点， PFOA。PFOA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 由鞘脂/磷脂和胆固醇组成的膜，作为膜蛋白的平台 以有效地发送下行信号。质膜脂筏在控制B细胞增殖中起着重要作用 activation.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点。在此，我们建议 中心假设，PFOA增加了不稳定的质膜脂筏的丰度， 幼稚B细胞。从机制上讲，这是由PFOA掺入脂筏，从而驱动脂筏- 相关的脂质进入质膜的非筏区。因此，PFOA会产生 脂质筏内的信号受体的有效定位的障碍，这是有效定位所需的。 幼稚B细胞的下游活化。为了验证这一假设，我们提出了两个目标，创新性地合并 体液免疫、毒理学和膜生物化学/生物物理学领域。目标1将研究如何 PFOA失调B细胞脂筏的稳定性和丰度。目标2将确定PFOA如何 脂质筏中特异性受体的募集失调及其功能后果。总体来说，这么高 风险/高回报研究将建立B细胞脂筏生物物理组织作为一个新的分子靶点， PFOA。这些研究将通过开辟一条新的研究途径， 了解PFOA和其他PFAS如何控制不同B细胞的脂筏组织和功能 群体和其他体液免疫的关键细胞类型。最终，这一系列的研究将改善我们的 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， 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.