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).

项目总结/摘要 小型未破裂颅内动脉瘤（UIA）（直径3-7 mm）的平均年发生率为 每年生长（≥1 mm）3%（范围：2-4年随访期间为7-21%）。1 -11例颅内动脉瘤（IA）， 与未扩大的相比，扩大的破裂风险增加了12-24倍。1 -11这些数据迫使 AHA/阿萨在其2015年指南中强烈建议对UIA进行手术或血管内治疗， 扩大，12，但需要这些昂贵的侵入性手术，这有相关的发病率和 如果能够开发药物治疗来预防IA生长或破裂，死亡率可能会受到限制。 根据一系列关于UIA的人类和动物研究数据，阿司匹林显示， 安全、廉价和有效的治疗，以减少IA的生长和破裂。 但是，女性和男性对阿萨的反应是否相同？答案是否定的。（A）我们的动物研究表明， 阿萨的生物学反应和阿萨降低IA风险的能力存在性别特异性差异 15（B）我们确定了对15-PGDH表达的影响是这种现象的潜在原因 并通过激活雌性小鼠中的这种酶和抑制雄性小鼠中的这种酶来逆转这些效应。 使用来自ISUIA队列的数据，在人类中证实了小鼠对阿萨的性别特异性反应， 阿萨在减少男性IA破裂方面比女性有效20%。15（D）血液的血清分析 从人IA囊内收集的15-PGDH显示，与 女性，证实了我们在小鼠中的发现，并增加了更多的证据表明，性别差异反应阿萨和15- PGDH是这一反应的可能解释。 我们的建议旨在验证这些主要假设：（1）15-PGDH的激活降低了IA的风险 a）减少PGE 2的有害表达和B）将PGE 2转化为15-酮PGE 2， 作为一种内源性的过氧化物酶体增殖物激活物受体激动剂，已知可降低动脉瘤破裂的风险;（2）15- 酮PGE 2对平滑肌细胞和巨噬细胞具有细胞特异性。 为了验证这些假设，我们将执行以下两个具体目标： 具体目的1：检验15-PGDH激活可同等降低男性UIA破裂风险的假设 和雌性WT小鼠，通过（A）降低PGE 2的表达和（B）增加15-酮PGE 2（其充当免疫调节剂）， 内源性的过氧化物酶体增殖体激活物受体激动剂，我们发现它降低了动脉瘤破裂的风险。具体目标2：测试 假设15-酮PGE 2（15-PGDH的最终副产物，其功能上充当一种抑制剂， 内源性过氧化物酶体增殖物激活剂（PPAR-A）主要作用于平滑肌细胞（SMC）和巨噬细胞（MΦ）。