BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10451495
• 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/10451495
• 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; 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; base; 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 我们的退伍军人群体的糖尿病患病率较高，患糖尿病的风险也较高 与一般人群相比，心血管疾病（CVD）由于糖尿病通常与糖尿病相关。 高胆固醇血症，建议糖尿病患者积极降低血浆低密度脂蛋白胆固醇（<100mg/dL） 实现这些严格的目标并达到高风险患者的低 LDL 胆固醇目标水平。 因此，需要采取新颖且优质的治疗干预措施来应对。 在过去的 15 年里，我的研究主要是针对心血管疾病高风险患者的高胆固醇血症。 重点研究肠道在维持体内胆固醇稳态中的作用 我们的目标是有效管理高胆固醇血症和相关疾病。 调节肠道胆固醇转运蛋白 NPC1L1 的新机制见解 NPC1L1 的增加。 在糖尿病等疾病中表达可增强胆固醇吸收并有助于 Zetia（依折麦布）是一种抑制 NPC1L1 活性的药物，可降低相关的高胆固醇血症。 然而，最近的研究支持血浆中的胆固醇水平“越低越好”的原则。 由于依折麦布仅阻断 NPC1L1 活性，因此与依折麦布一起降低 NPC1L1 的表达。 代表了一种进一步降低血浆胆固醇的有吸引力的治疗方法。 此类研究首次鉴定了 NPC1L1 启动子序列中的两个甾醇反应元件，并且 研究表明，甾醇反应元件结合蛋白 SREBP2 可以增加 NPC1L1 的表达。 最近还表明，肠道中的 NPC1L1 表达对 DNA 甲基化的变化敏感。 此外，我们还培育了一种新型转基因小鼠，其肠道特异性过度表达 SREBP2， 代表了一种独特的工具来检查肠道对胆固醇稳态的贡献。 表明仅在肠道中激活 SREBP2 就足以诱发高胆固醇血症 我们的研究还表明，饮食引起的肝损伤的易感性增加。 我们的研究小组通过 SREBP2 的过度激活来改变肠上皮细胞的干性。 取得突破性发现，表明 NPC1L1 胆固醇转运蛋白介导感染 这些研究产生了一项发明：依折麦布和其他 NPC1L1- 的新适应症。 我们的研究涉及调查肠道胆固醇。 自 2009 年以来，吸收一直由 VA 的绩效审查补助金持续资助。 该实验室还致力于研究回肠胆汁酸吸收的分子调节和 最近，我们研究了其放松管制对肝脏疾病发展的贡献（由 NIH R01 资助）。 开发了多种最先进的创新方法，例如实时测量胆汁酸转运 以及在活细胞中以及使用炔胆固醇进行基于点击化学的代谢。 研究旨在揭示健康和代谢中肠-肝相互作用的新途径 我的研究兴趣与我对教学和教育的积极参与得到了很好的补充。 我在弗吉尼亚州以及附属大学的使命中指导过许多本科生和研究生， 我和医师科学家、GI 研究员也是 VA 基础 F30 博士前奖学金的主要导师 医学博士/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积极合作。 来自多个学科的其他 VA 调查人员，与 VA 推进研究的使命相一致 值得注意的是，与普通人相比，退伍军人患心血管疾病的风险明显更高。 因此，我的研究计划是寻找降低血浆胆固醇的新方法。 及时且直接关系到退伍军人的健康，特别是患有糖尿病的退伍军人。