Mechanisms regulating the biosynthesis and signaling of oxylipins

氧脂素生物合成和信号传导的调节机制

• 批准号: 10710733
• 负责人: Benjamin Eric Tourdot
• 金额: $ 40.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710733
• 关键词: 12-HETE; Address; Anabolism; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Basic Science; Biological; Biological Models; Biological Process; Biology; Blood Platelets; Cardiovascular Diseases; Cells; Clinic; Clinical; Coagulation Process; Consensus; Cytochrome P450; Detection; Disease; Genes; Goals; Health; Human; Individual; Inflammation; Knowledge; Lipids; Lipoxygenase; Malignant Neoplasms; Megakaryocytes; Mixed Function Oxygenases; Modeling; Pattern; Play; Polyunsaturated Fatty Acids; Prognosis; Prostaglandin-Endoperoxide Synthase; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Translations; clinically relevant; disease diagnosis; innovation; insight; lipidomics; nanomolar; novel; novel therapeutic intervention; programs; tool; tumor progression

PROJECT SUMMARY Oxylipins are oxygenated bioactive lipids derived from polyunsaturated fatty acids that have diverse and integral functions in health and disease, including inflammation, cancer, and cardiovascular diseases. Oxylipins are short-lived, locally acting signaling molecules that are synthesized on demand by cyclooxygenases (COX), lipoxygenases (LOX), or cytochrome P450 monooxygenases. Advances in lipidomics have led to the detection of disease-specific changes in oxylipins. Although the identification of disease-specific changes in oxylipins has the power to be used for disease diagnosis, prognosis, or treatment, the translation of lipidomic studies into the clinic remains challenging due to a lack of biological understanding of oxylipins. To better understand the clinical relevance of disease-specific changes, we identified critical gaps in our knowledge that need to be addressed, including 1) what mechanisms regulate the coordinated synthesis of multiple oxylipins leading to cell-specific oxylipin patterns; and 2) how the signals elicited from individuals oxylipins are integrated into biological functions. To address these gaps in our knowledge, the long-term goal of our research program is to decipher the signaling mechanism responsible for the synthesis and function of individual oxylipins to understand the functional consequence of their alterations in diseases. Without further mechanistic insights into disease-specific changes in oxylipins, it is unlikely novel oxylipins will be effectively targeted for clinical purposes. Platelets are the ideal model system to study oxylipin biology because they produce nanomolar levels of approximately 15 oxylipins from COX and 12(S)-lipoxygenase (12-LOX) and offer a simplified model to study the biological consequences of oxylipin dysregulation. In this proposal, we will focus on the function of 12-LOX and its arachidonic acid (AA)-derived metabolite, 12-HETE, which have broad clinical and biological significance. However, due to the lack of consensus on the function of 12-HETE, the mechanism by which 12- LOX contributes to inflammation, cancer progression, and clotting is controversial and represents a substantial knowledge gap. This proposal will study 12-LOX and 12-HETE as a prototypical examples to address its role in disease, and develop tools to characterize the function of oxylipins by using gene-edited human megakaryocytes, which have been shown to faithfully recapitulate the donor-derived platelets. Our short-term goals are to 1) determine the intracellular mechanisms used to release and deliver substrate to 12-LOX and 2) identify the downstream signaling pathway(s) activated by 12-HETE in platelets. Our studies will provide valuable insight into the mechanistic understanding of oxylipin synthesis and function that could ultimately aid in developing new therapeutic approaches for a broad range of diseases.

项目概要 氧脂质是源自多不饱和脂肪酸的含氧生物活性脂质，具有多种和 在健康和疾病中发挥着不可或缺的作用，包括炎症、癌症和心血管疾病。氧脂质 是短寿命、局部作用的信号分子，由环氧合酶 (COX) 按需合成， 脂加氧酶 (LOX) 或细胞色素 P450 单加氧酶。脂质组学的进展导致了检测 氧脂质的疾病特异性变化。尽管氧脂质的疾病特异性变化的鉴定已 用于疾病诊断、预后或治疗的能力，将脂质组学研究转化为 由于缺乏对氧脂素的生物学了解，临床仍然具有挑战性。为了更好地理解 由于疾病特定变化的临床相关性，我们发现了我们知识中的关键差距，需要弥补 解决了这些问题，包括 1) 哪些机制调节多种氧脂质的协调合成，从而导致 细胞特异性氧脂质模式； 2）如何将个体氧脂蛋白引发的信号整合到 生物学功能。为了弥补我们知识上的这些差距，我们研究计划的长期目标是 破译负责单个氧脂蛋白合成和功能的信号机制 了解它们在疾病中的改变的功能后果。没有进一步的机械见解 由于氧脂质的疾病特异性变化，新型氧脂质不太可能有效地用于临床 目的。血小板是研究氧脂质生物学的理想模型系统，因为它们产生纳摩尔 来自 COX 和 12(S)-脂氧合酶 (12-LOX) 的约 15 种氧脂质水平，并提供简化模型 研究氧脂质失调的生物学后果。在本提案中，我们将重点关注以下功能： 12-LOX 及其花生四烯酸 (AA) 衍生代谢物 12-HETE，具有广泛的临床和生物学作用 意义。然而，由于对12-HETE的功能缺乏共识，12-HETE的作用机制尚不清楚。 LOX 会导致炎症、癌症进展和凝血，这一点存在争议，但代表了重要的因素。 知识差距。该提案将研究 12-LOX 和 12-HETE 作为典型例子，以解决其在 疾病，并开发工具通过使用基因编辑的人类来表征氧脂质的功能 巨核细胞已被证明能够忠实地再现供体来源的血小板。我们的短期 目标是 1) 确定用于释放和递送底物至 12-LOX 的细胞内机制，以及 2) 识别血小板中 12-HETE 激活的下游信号通路。我们的研究将提供 对氧脂素合成和功能的机制理解的宝贵见解，最终可能有助于 为多种疾病开发新的治疗方法。