15-PGDH as a better therapeutic target than aspirin in decreasing risk of intracranial aneurysm rupture in men and women equally

15-PGDH 是比阿司匹林更好的治疗靶点，可同等降低男性和女性颅内动脉瘤破裂的风险

• 批准号: 10584534
• 负责人: David M. Hasan
• 金额: $ 35.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584534
• 关键词: Acceleration; Agonist; Aneurysm; Animal Model; Animals; Antiinflammatory Effect; Antioxidants; Aspirin; Attenuated; Biological; Blood; Cells; Cerebral Aneurysm; Clinical; Clinical Research; Clinical Trials; Data; Diameter; Dinoprostone; Dominant-Negative Mutation; Double-Blind Method; Endothelium; Enzymes; Female; Gene Expression; Genetic; Genetically Engineered Mouse; Growth; Guidelines; Health; Human; Incidence; Inflammatory; Intracranial Aneurysm; Macrophage; Mediating; Morbidity - disease rate; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Observational Study; Operative Surgical Procedures; PTGS2 gene; Pathway interactions; Pharmacologic Substance; Phase; Placebos; Play; Procedures; Process; Randomized; Recommendation; Research; Risk; Risk Reduction; Role; Rupture; Ruptured Aneurysm; Series; Serum; Sex Differences; Smooth Muscle Myocytes; Stroke; Testing; Translations; Woman; antagonist; cellular targeting; cohort; cost; effective therapy; follow-up; improved; innovation; male; men; mortality; mouse model; novel; pre-clinical; preclinical study; prevent; prospective; protective effect; response; sex; therapeutic target

PROJECT SUMMARY / ABSTRACT Small unruptured intracranial aneurysms (UIAs) (3–7 mm in diameter) have an average annual likelihood of growth (≥1 mm) of 3% per year (range: 7–21% over 2–4 years of follow-up).1-11 Intracranial aneurysms (IA) that enlarge have 12–24 times increased risk of rupture compared to those that do not.1-11 These data compelled the AHA/ASA in their 2015 guidelines to strongly recommend surgical or endovascular treatment of UIAs that enlarge,12 but the need for these expensive invasive procedures, which have associated morbidity and mortality, could be limited if pharmaceutical treatments could be developed to prevent IA growth or rupture. Based on data from a series of studies in humans and animals regarding UIAs, Aspirin has shown to safe, inexpensive, and effective treatment to decrease IA growth and rupture. But do women and men respond equally to ASA? The answer is NO. (A) Our animal study revealed that there are sex-specific differences in the biologic response to ASA and the ability of ASA to reduce the risk of IA rupture in mice.15 (B) We identified effects on expression of 15-PGDH as a potential cause of this phenomenon and reversed these effects by activating this enzyme in female mice and inhibiting it in male mice.15 (C) The finding of sex-specific responses to ASA in mice was confirmed in humans using data from ISUIA cohort, with ASA being 20% more effective in reducing IA rupture in males than females.15 (D) Serum analysis of blood collected from within human IA sacs showed significant elevation of 15-PGDH in males when compared to females, confirming our findings in mice and adding more evidence of sex differential response to ASA and 15- PGDH as potential explanation for this response.23 Our proposal seeks to test these primary hypotheses: (1) activation of 15-PGDH decreases the risk of IA rupture by: a) decreasing the harmful expression of PGE2 and b) converting PGE2 to 15-keto PGE2 which acts as an endogenous agonist of PPAR, which is known to decrease the risk of IA rupture; (2) the effect of 15- keto PGE2 is cell-specific to smooth muscle cells and macrophages. To test these hypotheses, we will perform these two specific aims: Specific Aim 1: Test the hypothesis that activation of 15-PGDH decreases risk of UIA rupture equally in male and female WT mice by (A) decreasing expression of PGE2 and (B) increasing 15-keto PGE2 which acts as an endogenous agonist of PPAR which we showed decreases the risk of IA rupture. Specific Aim 2: Test the hypothesis that the effect of 15-keto PGE2 (final byproduct of 15-PGDH which functionally acts as an endogenous PPAR activator) primarily acts in smooth muscle cells (SMC) and macrophages (MΦ).

项目摘要 /摘要 小颅内动脉瘤（UIA）（直径3-7毫米）的平均年可能性 每年3％的增长（≥1毫米）（范围：在2 - 4年的随访中7–21％）。1-11颅内动脉瘤（IA） 与没有的扩大相比，扩大的破裂风险增加了12-24倍。1-11这些数据强迫 AHA/ASA在其2015年指南中，强烈建议对UIA的外科手术或血管内治疗 扩大，12，但需要这些昂贵的侵入性程序，这些程序具有发病率和 如果可以开发药物治疗以防止IA生长或破裂，则死亡率可能会受到限制。 基于来自人类和动物有关UIA的一系列研究的数据，阿司匹林已证明 安全，廉价且有效的治疗方法，以减少IA的生长和破裂。 但是，男女对ASA的反应是否同样反应？答案是否定的。 （a）我们的动物研究表明 对ASA的生物反应存在性别特定的差异以及ASA降低IA风险的能力 小鼠破裂。15（b）我们确定对15-pgdh表达的影响是这种现象的潜在原因 并通过在雌性小鼠中激活这种酶来逆转这些作用，并抑制雄性小鼠。15（c） 在人类中，使用ISUIA队列的数据证实了小鼠对ASA的性别特异性反应的发现， ASA在减少男性的IA破裂时比女性高20％。15（d）血液分析 与人IA囊中收集 女性，证实我们在小鼠中的发现，并增加了对ASA和15-的性别差异反应的更多证据 PGD​​H作为此反应的潜在解释。23 我们的建议旨在检验这些主要假设：（1）15-PGDH的激活降低了IA的风险 破裂方法：a）减少PGE2和b）将PGE2转换为15-Keto PGE2的有害表达 作为PPAR的内源性激动剂，已知会降低IA破裂的风险； （2）15-的影响 酮PGE2是平滑肌细胞和巨噬细胞的细胞特异性。 为了检验这些假设，我们将执行这两个具体目标： 特定目的1：检验以下假设：15-PGDH的激活降低了男性中UIA破裂的风险 （a）降低PGE2表达和（b）增加15-Keto PGE2的雌性WT小鼠，它充当 我们表明的PPAR的内源性激动剂会下降IA破裂的风险。特定目标2：测试 假设15-酮PGE2的作用（15-PGDH的最终副产品在功能上充当 内源性PPAR激活剂）主要作用于平滑肌细胞（SMC）和巨噬细胞（Mφ）中。