BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10618249
• 负责人: Waddah A. Alrefai
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618249
• 关键词: Address; Alkynes; Atherosclerosis; Award; Bile Acids; Binding Proteins; Blood; Cardiovascular Diseases; Caring; Cells; Chemistry; Cholesterol; Cholesterol Homeostasis; Collaborations; Complement; Complex; Coronary heart disease; DNA Methylation; Development; Diabetes Mellitus; Diet; Discipline; Disease; Doctor of Philosophy; Dyslipidemias; Education; Educational process of instructing; Epithelial Cells; Equilibrium; Fellowship; Functional disorder; Funding; Future; General Population; Generations; Genes; Goals; Grant; Grant Review; Health; Hepatitis C; Hepatitis C Therapy; Hepatitis C virus; High Prevalence; Homeostasis; Infection; Intestines; LDL Cholesterol Lipoproteins; Laboratories; Lipids; Liver; Liver diseases; Maintenance; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Methods; Mission; Molecular; Molecular Biology Techniques; Nature; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Physiology; Plasma; Predisposition; Prevalence; Process; Promoter Regions; Recommendation; Regulation; Research; Research Personnel; Response Elements; Risk; Risk Factors; Role; Scientist; Sterols; Stroke; Students; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; United States National Institutes of Health; Universities; Veterans; absorption; cardiovascular disorder risk; career; cholesterol absorption; cholesterol transporters; diabetic patient; ezetimibe; fatty liver disease; gut-liver axis; high risk; hypercholesterolemia; inhibitor; innovation; insight; interest; intestinal epithelium; invention; liver development; liver injury; military veteran; mouse model; novel; novel strategies; overexpression; patient population; pre-doctoral; programs; stem cells; stemness; therapeutic target; tool; undergraduate student

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.

概括 我们的退伍军人人口患糖尿病的患病率更高，发展的风险增加 与普通人群相比，心血管疾病（CVD）。由于糖尿病通常与 高胆固醇血症，血浆LDL-胆固醇的积极降低（<100mg/dl）用于糖尿病 患者。实现这些严格的目标，并达到高风险的靶向低LDL胆固醇水平 患者仍然挑战。必须进行新颖和优质的治疗干预措施来管理 CVD高风险患者的高胆固醇血症。在过去的15年中，我的研究主要 专注于研究肠道在维持体内胆固醇稳态中的作用 有效管理高胆固醇血症和相关疾病的目标。我们的研究产生了几个 肠道胆固醇转运蛋白NPC1L1调节的新机械见解。 NPC1L1的增加 糖尿病等疾病中的表达可增强胆固醇的抽象，并有助于 相关的高胆固醇血症。抑制NPC1L1活性的药物Zetia（Ezetimibe）下降 血液中的胆固醇水平。但是，最近的研究支持血浆“较低的原则”原理 胆固醇。由于ezetimibe仅阻止NPC1L1活性，因此与ezetimibe一起降低NPC1L1的表达 代表了一种有吸引力的治疗方法，可进一步降低血浆胆固醇。在这方面，我们的 研究首先是在NPC1L1启动子序列和 表明NPC1L1的表达通过固醇反应元件结合蛋白SREBP2增加。我们 最近还表明，肠中的NPC1L1表达对DNA甲基化的改变敏感。 此外，我们已经产生了一种新型的转基因小鼠，具有SREBP2的肠特异性过表达 代表了检查肠道对胆固醇稳态的贡献的独特工具。我们的研究 表明这仅在肠中激活SREBP2足以诱导高胆固醇血症 并增加了对饮食诱导的肝损伤的敏感性。我们的研究还表明 肠上皮细胞的干性通过SREBP2的过度激活。我们的小组为研究做出了贡献 导致突破性发现表明NPC1L1胆固醇转运蛋白介导了感染 丙型肝炎病毒。这些研究引起了邀请：Ezetimibe和其他NPC1L1-的新指示。 抑制剂作为丙型肝炎病毒感染的治疗。我们的研究与研究肠道胆固醇有关 自2009年以来，弗吉尼亚州的优异审查赠款一直在不断资助抽象。 该实验室还专注于研究尿酸酸滥用的分子调节和 其放松管制对肝病发展的贡献（由NIH资助）。最近，我们 已经开发了几种最先进的创新方法，例如实时测量胆汁酸转运 在活细胞以及使用芦荟胆固醇接近化学的代谢中。我们的未来 研究针对揭示新的途径，包括健康和代谢中的肠肝相互作用 疾病。我积极参与教学和教育，我的研究兴趣已经很好地完成了 在弗吉尼亚州以及会员大学的任务。我指导了许多本科生和研究生， 物理科学家，GI研究员和我也是F30基于VA的F30奖学金的主要精神 MD/PHD候选人（F30 DK117535）。我的研究计划已经与 来自多个学科的其他基于VA的调查员，与VA的使命保持一致 为了照顾我们的退伍军人。值得注意的是，与 一般人口。因此，我找到减少血浆胆固醇新颖手段的研究计划是 及时，直接与退伍军人的健康有关，尤其是糖尿病的退伍军人。