BLRD Research Career Scientist Award Application

摘要 我们的退伍军人有更高的糖尿病患病率和更高的患病风险 心血管疾病(CVD)与普通人群相比。因为糖尿病通常与 糖尿病患者建议高胆固醇血症，积极降低血浆低密度脂蛋白-胆固醇(&lt；100 mg/dL) 病人。实现这些严格目标，并在高风险情况下达到目标低密度脂蛋白胆固醇水平 患者仍然具有挑战性。因此，新的和更好的治疗干预是有必要管理的。 心血管疾病高危患者的高胆固醇血症。在过去的15年里，我的研究主要是 重点研究肠道在维持体内胆固醇稳态中的作用。 目标是有效地管理高胆固醇血症和相关疾病。我们的研究已经得出了几个 肠道胆固醇转运蛋白NPC1L1调控的新机制研究。NPC1L1的增加 糖尿病等疾病中的表达增强了胆固醇的吸收，并有助于 伴发高胆固醇血症。抑制NPC1L1活性的药物Zetia(Ezetimibe)减少 血液中的胆固醇水平。然而，最近的研究支持血浆“越低越好”的原则。 胆固醇。由于ezetimibe仅阻断NPC1L1活性，因此与ezetimibe一起降低NPC1L1的表达 为进一步降低血浆胆固醇提供了一种有吸引力的治疗方法。在这方面，我们的 首次在NPC1L1启动子序列和NPC1L1启动子序列中发现两个斯特罗反应元件 结果表明，Sterol反应元件结合蛋白SREBP2上调了NPC1L1的表达。我们 最近也表明NPC1L1在肠道中的表达对DNA甲基化的变化很敏感。 此外，我们还培育了一种新型转基因小鼠，该小鼠具有肠道特异的SREBP2过表达 代表了一个独特的工具，以检查肠道对胆固醇稳态的贡献。我们的研究 这表明，SREBP2在肠道中的激活仅足以引起高胆固醇血症 并增加了对饮食诱导的肝损伤的易感性。我们的研究还表明， SREBP2过度激活对肠上皮细胞干性的影响。我们小组对这些研究做出了贡献 导致了一项突破性的发现，表明NPC1L1胆固醇转运体介导了 丙型肝炎病毒。这些研究产生了一项发明：Ezetimibe和其他NPC1L1-的新适应症- 丙型肝炎病毒感染的抑制剂治疗。我们关于调查肠道胆固醇的研究 自2009年以来，吸收一直由退伍军人管理局的功绩审查赠款提供资金。正在进行的研究 实验室还重点研究了回肠胆汁酸吸收的分子调节和 其放松管制对肝病发展的贡献(由美国国立卫生研究院R01资助)。最近，我们 我开发了几种最先进的创新方法，如实时测量胆汁酸转运 而在活细胞中，以及基于点击化学的代谢方法，使用的是炔胆固醇。我们的未来 研究旨在解开肠道-肝脏相互作用在健康和代谢中的新途径 疾病。我的研究兴趣因我积极参与教学和教育而得到很好的补充 在退伍军人事务部和附属大学的使命。我曾经指导过很多本科生和研究生， 内科科学家、GI研究员和我也是退伍军人管理局F30博士前奖学金的主要导师 博士/博士候选人(F30 DK117535)。我的研究项目与以下机构建立了强有力的合作 来自多个学科的其他退伍军人事务部调查人员，与退伍军人事务部推进研究的使命保持一致 照顾我们的退伍军人。值得注意的是，与退伍军人相比，退伍军人患心血管疾病的风险明显更高。 普通人口。因此，我的研究计划是寻找降低血浆胆固醇的新方法 及时和直接关系到退伍军人，特别是患有糖尿病的退伍军人的健康。

Summary Our Veteran population has higher prevalence of diabetes mellitus and increased risk for developing cardiovascular diseases (CVD) as compared to general population. Since diabetes is generally associated with hypercholesterolemia, aggressive lowering of plasma LDL-cholesterol (<100mg/dL) is recommended for diabetic patients. Achieving these stringent goals and reaching the targeted low LDL cholesterol levels in high risk patients remains challenging. Thus, novel and superior therapeutic intervention is warranted to manage hypercholesterolemia in patients with high risk for CVDs. Over the past 15 years, my studies have primarily focused on investigating the roles of the gut in the maintenance of cholesterol homeostasis in the body with a goal to effectively manage hypercholesterolemia and associated diseases. Our studies have yielded several novel mechanistic insights in regulation of intestinal cholesterol transporter NPC1L1. The increase in NPC1L1 expression in diseases such as diabetes mellitus enhances cholesterol absorption and contributes to the associated hypercholesterolemia. Zetia (ezetimibe), the drug which inhibits NPC1L1 activity, decreases cholesterol levels in the blood. However, recent studies supported the principle of “the lower is better” for plasma cholesterol. Since ezetimibe only blocks NPC1L1 activity, decreasing NPC1L1 expression along with ezetimibe represents an attractive therapeutic approach for a further reduction in plasma cholesterol. In this regard, our studies were first of its kind to identify two Sterol Response Elements in the NPC1L1 promoter sequence and showed that NPC1L1 expression is increased by the Sterol Response Element Binding Protein SREBP2. We have also recently shown that NPC1L1 expression in the intestine is sensitive to alterations in DNA methylation. Further, we have generated a novel transgenic mouse with intestine-specific overexpression of SREBP2 that represents a unique tool to examine the contributions of the intestine to cholesterol homeostasis. Our studies showed that this the activation of SREBP2 in the intestine only was sufficient to induce hypercholesterolemia and increased susceptibility to diet-induced liver injury. Our studies also demonstrated an increase in the stemness of intestinal epithelial cells by the overactivation of SREBP2. Our group contributed to the studies that led to a breakthrough discovery showing that NPC1L1 cholesterol transporter mediates the infection with hepatitis C virus. These studies resulted in an invention: New Indication for Ezetimibe and other NPC1L1- inhibitors as treatment for hepatitis C virus infection. Our studies pertaining to investigating intestinal cholesterol absorption have been continuously funded by a Merit Review grant from the VA since 2009. Ongoing studies in the laboratory are also focused on investigating the molecular regulation of ileal bile acid absorption and the contribution of its deregulation to the development of liver diseases (funded by R01 from NIH). Recently, we have developed several state-of-the art innovative methods such as measuring bile acid transport in real time and in living cells as well as click chemistry based metabolic approached using alkyne cholesterol. Our future studies are directed at unraveling novel pathways encompassing gut-liver interaction in health and metabolic diseases. My research interests are very well complemented by my active involvement in teaching and education mission at the VA as well as at the affiliate University. I have mentored a number of undergrad and grad students, physician scientists, GI Fellows and I am also the primary mentor on F30 predoctoral fellowship for VA based MD/PhD candidate (F30 DK117535). My research program has established strong active collaborations with other VA based investigators from multiple disciplines that align with the mission of VA in advancing the research for the care of our veterans. Notably, the risk for CVD is significantly higher in veterans as compared to the general population. Therefore, my research program to find novel means to decrease plasma cholesterol is timely and directly relevant to the health of veterans in general and, particularly, veterans with diabetes mellitus.