A novel mechanism for rapid increase of brain prostanoid levels

描述（由申请人提供）：前列腺素类（PG）是调节许多生理和病理过程的重要信号分子。PG介导疼痛、发热、炎症，并参与多种临床病症的发展，包括癌症、炎症、神经退行性疾病、中枢神经系统损伤和神经精神病症。然而，调节大脑PG水平的机制知之甚少。我们的长期目标是了解大脑PG水平调节的机制，并概述用于治疗各种神经病理生理条件的药物的潜在新的治疗靶点。本申请的目的是阐明刺激后脑前列腺素类立即快速增加（<1分钟）的机制。在本申请中，我们假设PG释放的新途径。我们的中心假设是，前列腺素质量的快速增加是通过动员快速释放的预先形成的PG库而发生的，这些PG被发现酯化在磷脂上。我们在初步研究中提出的发现支持了这一假设。我们发现：1. PG被酯化到磷脂上[注意这些不是异前列烷]; 2.酯化PG在体内刺激后迅速释放; 3.储存在磷脂上的PG来源于COX 1/2; 4.外源添加的PG被酯化到细胞磷脂上; 5.花生四烯酸（20：4 n-6）释放不是炎症反应期间PG质量初始增加所必需的。前列腺素类释放的假设新途径解决了与传统PG释放途径相关的一些矛盾，并且与已知的大脑中PG快速形成更一致。重要的是，我们提出的新途径是指在刺激后组织反应的早期阶段PG质量增加的快速增加，并且不反对传统途径在组织反应的晚期阶段的作用。然而，由于PG质量的初始快速增加可能引发随后的组织反应阶段，因此所提出的PG释放的新途径无疑与PG形成相关的组织损伤反应的后期阶段有关。将通过以下特定目的检验中心假设：特定目的1：确定脑细胞和组织以酯化形式储存PG的能力;特定目的2：确定负责从磷脂储存池中释放PG的酶系统;拟议的工作是创新的，因为它检查了一种新的途径，PG释放从预先形成的池酯化到磷脂，以前没有解决的他人这些结果将是重要的，因为该项目的成功完成将增强目前关于脑PG水平调节的观点，并将揭示磷脂在PG释放中的新功能。此外，它将概述用于治疗各种神经病理生理条件的药物的潜在新的治疗靶点，并将增强我们对这些条件下的机制的理解。公共卫生相关性：我们提出的工作的相关性是，它检查了一种新的机制，通过前列腺素释放从预先形成的池酯化到磷脂，以前没有解决的大脑前列腺素水平的快速增加。这一点很重要，因为前列腺素类与大量神经退行性疾病有关。这些结果将是显着的，因为它们将提高目前的传统观点，关于脑前列腺素水平的调节，概述了潜在的新的治疗目标，用于治疗各种各样的神经病理生理条件的药物，并提高我们对这些条件下的机制的理解。

DESCRIPTION (provided by applicant): Prostanoids (PG) are important signaling molecules that regulate many physiological and pathological processes. PG mediate pain, fever, inflammation and are involved in the development of a broad range of clinical disorders including cancer, inflammation, neurodegenerative diseases, central nervous system injury, and neuropsychiatric conditions. However, the mechanism that regulates brain PG levels is poorly understood. Our long-term goal is to understand the mechanism underlying the regulation of brain PG levels and to outline potentially new therapeutic targets for drugs used in the treatment of a wide variety of neuropathophysiological conditions. The objective of this application is to elucidate the mechanisms accounting for the immediate, rapid increase (<1 min) in brain prostanoids upon stimulation. In this application, we hypothesize a novel pathway for PG release. Our Central Hypothesis is that the rapid increase in prostanoid mass occurs via mobilization of a rapidly releasable pool of preformed PG found esterified onto phospholipids. Our findings presented in the Preliminary Studies support this hypothesis. We found that: 1. PG are esterified onto phospholipids [Note these were not isoprostanes]; 2. esterified PG are rapidly released upon stimulation in vivo ; 3. PG stored on phospholipids are derived from COX1/2; 4. exogenously added PG are esterified onto cellular phospholipids; 5. arachidonic acid (20:4n-6) release is not required for this initial increase in PG mass during the inflammation response. The hypothesized novel pathway for prostanoid release addresses some of the contradictions associated with the traditional pathway of PG release and is more consistent with the known rapid formation of PG in brain. Importantly, our proposed novel pathway refers to the rapid increase in PG mass increase at early phase of tissue response upon stimulation, and does not argue against the role of traditional pathway at the late phases of tissue response. However, because the initial rapid increase in PG mass may trigger consequent phases of tissue response, the proposed novel pathway for PG release is undoubtedly linked to the later phases of tissue injury response with regards to PG formation. The central hypothesis will be tested by the following specific aims: Specific Aim 1: Determine the capacity of brain cells and tissue for PG storage in esterified form; Specific Aim 2: Determine enzymatic systems responsible for PG release from phospholipid storage pool; The proposed work is innovative because it examines a novel pathway for PG release from preformed pool esterified onto phospholipids that has not been previously addressed by others. These results will be significant because the successful completion of the project will enhance the current view regarding the regulation of brain PG levels and will reveal a new function for phospholipids in PG release. Also, it will outline potentially new therapeutic targets for drugs used in the treatment of a wide variety of neuropathophysiological conditions and will enhance our understanding of the mechanisms underlying these conditions. PUBLIC HEALTH RELEVANCE: The relevance of our proposed work is that it examines a novel mechanism for a rapid increase of brain prostanoid levels through prostanoid release from preformed pool esterified onto phospholipids that has not been previously addressed by others. This is important because of the association of prostanoids with a large number of neurodegenerative diseases. These results will be significant because they will enhance the current traditional view regarding the regulation of brain prostanoid levels, outline potentially new therapeutic targets for drugs used in the treatment of a wide variety of neuropathophysiological conditions, and enhance our understanding of the mechanisms underlying these conditions.