BLRD Research Career Scientist Award Application

总结 我们的退伍军人人群糖尿病患病率较高， 心血管疾病（CVD）与一般人群相比。由于糖尿病通常与 高胆固醇血症，积极降低血浆LDL-胆固醇（<100 mg/dL）被推荐用于糖尿病 患者实现这些严格的目标，并在高风险人群中达到目标低LDL胆固醇水平 患者仍然具有挑战性。因此，需要新的和上级的治疗干预来管理 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， 目的是有效管理高胆固醇血症和相关疾病。我们的研究发现 调节肠道胆固醇转运蛋白NPC 1 L1的新机制见解。NPC 1 L1的增加 在疾病如糖尿病中的表达增强胆固醇吸收，并有助于 相关的高胆固醇血症。Zetia（依折麦布），抑制NPC 1 L1活性的药物， 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 胆固醇由于依折麦布仅阻断NPC 1 L1活性，因此与依折麦布一起沿着NPC 1 L1表达降低 代表了进一步降低血浆胆固醇的有吸引力的治疗方法。在这方面， 这些研究首次鉴定了NPC 1 L1启动子序列中的两个甾醇应答元件， 显示NPC 1 L1表达通过固醇反应元件结合蛋白SREBP 2增加。我们 最近还表明，NPC 1 L1在肠道中的表达对DNA甲基化的改变敏感。 此外，我们已经产生了一种新的转基因小鼠，其具有SREBP 2的精氨酸特异性过表达， 代表了一个独特的工具，检查肠道的贡献，胆固醇稳态。我们的研究 表明仅在肠中激活SREBP 2就足以诱导高胆固醇血症 以及增加对饮食引起的肝损伤的易感性。我们的研究还表明， SREBP 2过度激活导致肠上皮细胞干性。我们的团队参与了 导致了一个突破性的发现，显示NPC 1 L1胆固醇转运蛋白介导的感染， 丙型肝炎病毒这些研究产生了一项发明：依折麦布和其他NPC 1 L1的新适应症- 抑制剂作为丙型肝炎病毒感染的治疗方法。我们的研究有关调查肠道胆固醇 自2009年以来，吸收一直由VA的绩效审查补助金提供资金。正在进行的研究 实验室还专注于研究回肠胆汁酸吸收的分子调节， 其放松管制对肝脏疾病发展的贡献（由NIH的R 01资助）。最近我们 已经开发了几种最先进的创新方法，例如真实的时间测量胆汁酸转运 以及在活细胞中以及使用炔胆固醇的基于点击化学的代谢方法。我们的未来 研究旨在揭示新的途径，包括健康和代谢中的肠道-肝脏相互作用。 疾病我的研究兴趣与我积极参与教学和教育工作相辅相成 退伍军人事务部和附属大学的使命。我指导过很多本科生和格拉德生， 医生科学家，GI研究员，我也是基于VA的F30博士前奖学金的主要导师 MD/PhD候选人（F30 DK 117535）。我的研究项目与以下机构建立了强有力的积极合作关系： 来自多个学科的其他VA研究人员，与VA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。 一般人口。因此，我的研究计划，以寻找新的手段，以降低血浆胆固醇是 及时和直接关系到退伍军人的健康，特别是糖尿病退伍军人。

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.