Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State

糖尿病患者死亡的主要原因是心血管疾病（CVD）。我们的长期目标是 确定预防糖尿病患者CVD的新治疗靶点。在第一个赠款周期，我们 确定酶黄素含单加氧酶3（FMO 3）作为糖尿病相关的潜在介导剂， 心血管疾病通过一个无偏见的转录组学方法。在第二个资助周期中，我们发现， FMO 3通过关键代谢物三甲胺N-氧化物（TMAO）发挥其许多作用;我们进一步发现， 内质网应激激酶（PERK）是TMAO的受体。 多项临床研究表明，TMAO随着胰岛素抵抗而增加， 动脉粥样硬化，证实了这一途径在人类中失调，并表明抑制动脉粥样硬化， FMO 3/TMAO通路可能具有有益作用。氧化三甲胺是由其代谢产物三甲胺 (TMA)，这反过来又由肠道微生物产生。因此，一个有吸引力的策略是抑制 由肠道微生物产生TMA。在我们未发表的初步数据中，我们筛选了一种药物 图书馆使用再利用药物的好处是，它们已经被认为对人类是安全的， 把他们带进诊所所需的时间和费用。我们发现了一种化合物， 一种能产生TMA并能降低小鼠体内TMAO水平的酶。 当前周期的目标是填补我们对人类社会的机械理解中仍然存在的关键空白。 TMAO通路的影响，并测试降低TMAO的治疗潜力。我们假设TMAO， 增加与糖尿病，诱导PERK促进血脂异常，炎症和糖尿病相关 动脉粥样硬化我们的目的是阐明PERK促进代谢功能障碍的机制; 确定肝脏缺失PERK在多大程度上可以预防TMAO诱导的血脂异常、炎症 和动脉粥样硬化;并测试在我们的药物再利用筛选中发现的新化合物是否可以 预防糖尿病诱导的小鼠动脉粥样硬化。我们希望这些研究将导致一个新的，正交的， 降低糖尿病患者CVD风险的方法。

The leading cause of death in diabetic patients is cardiovascular disease (CVD). Our long-term goal is to identify new therapeutic targets for the prevention of CVD in diabetic patients. In the first grant cycle, we identified the enzyme flavin-containing monooxygenase 3 (FMO3) as a potential mediator of diabetes-associated cardiovascular disease via a non-biased transcriptomics approach. In the second grant cycle, we found that FMO3 exerted many of its effects via the key metabolite, trimethylamine N-oxide (TMAO); we further found the endoplasmic reticulum stress kinase, PERK, to be a receptor for TMAO. Multiple clinical studies have now shown that TMAO is increased with insulin resistance, as well as atherosclerosis, confirming that this pathway is dysregulated in humans, and suggesting that inhibition of the FMO3/TMAO pathway may have beneficial effects. TMAO is synthesized from the metabolite trimethylamine (TMA), which is in turn produced by the gut microbes. Therefore, an attractive strategy would be to inhibit the production of TMA by the gut microbes. In our unpublished, preliminary data, we screened a drug repurposing library. The advantage of using repurposed drugs is that they are already known to be safe in humans, reducing the time and expense needed to bring them into the clinic. We identified a compound that inhibits the microbial enzyme that generates TMA and can lower TMAO levels in mice. The goals of the current cycle are to fill the key remaining gaps in our mechanistic understanding of the TMAO pathway, and to test the therapeutic potential of lowering TMAO. We hypothesize that TMAO, which is increased with diabetes, induces PERK to promote dyslipidemia, inflammation and diabetes-associated atherosclerosis. Our aims are to elucidate the mechanisms by which PERK promotes metabolic dysfunction; to determine the extent to which hepatic deletion of PERK can prevent TMAO-induced dyslipidemia, inflammation and atherosclerosis; and to test whether the novel compound identified in our drug repurposing screen can prevent diabetes-induced atherosclerosis in mice. We expect that these studies will lead to a novel, orthogonal approach to reducing CVD risk in patients with diabetes.