Phosphatidylcholine and cholesterol ester biomarkers of type 2 diabetes and preventive treatment effects

2型糖尿病的磷脂酰胆碱和胆固醇酯生物标志物及预防治疗效果

• 批准号: 10301041
• 负责人: Zsu-Zsu Chen
• 金额: $ 16.57万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301041
• 关键词: Address; Adult; Advisory Committees; Aromatic Amino Acids; Behavior Therapy; Behavioral; Biological Markers; Cardiometabolic Disease; Cholesterol Esters; Clinical; Clinical Research; Clinical Trials; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease Progression; Endocrinology; Faculty; Foundations; Future; Genetic; Genetic Determinism; Genetic study; Glycosylated hemoglobin A; Goals; Heterogeneity; Hospitals; Human; Impairment; Incidence; Individual; Individual Differences; Insulin Resistance; Intervention; Israel; Lecithin; Life Style; Lipids; Mass Spectrum Analysis; Master of Public Health; Measurement; Measures; Medical center; Mendelian randomization; Mentors; Metabolic Pathway; Metformin; Modeling; Molecular; Molecular Profiling; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Phenotype; Phospholipids; Physicians; Pilot Projects; Plasma; Population; Prediabetes syndrome; Prevalence; Prevention; Preventive treatment; Prospective cohort study; Randomized; Research; Research Design; Risk; Risk Factors; Sampling; Scientist; Statistical Models; Subgroup; Testing; Training; Training Programs; Translational Research; United States National Institutes of Health; Variant; Work; base; biomarker discovery; blood glucose regulation; burden of illness; career development; clinical biomarkers; clinical decision-making; clinical phenotype; clinical risk; cohort; control trial; diabetes mellitus genetics; diabetes prevention program; diabetes risk; effective therapy; experience; fasting glucose; fasting plasma glucose; follow-up; functional genomics; genomic locus; high risk; impaired glucose tolerance; insight; interest; laboratory experience; member; metabolomics; multiple omics; novel; novel marker; novel strategies; population based; predictive marker; predictive modeling; prevent; preventive intervention; prospective; recruit; response; skills; small molecule; symposium; trait; treatment choice; treatment effect; treatment strategy; trial comparing

PROJECT SUMMARY/ABSTRACT Background: The increasing incidence and prevalence of type 2 diabetes (T2D) can be mitigated by successful prevention with behavioral changes or pharmacotherapy in individuals that are at high risk. Identifying a specific individual’s risk for diabetes and which preventive treatment will be most effective, however, remains a clinical dilemma. Metabolite biomarkers represent a novel approach to addressing these clinical challenges and may also reveal mechanisms of disease development. This five-year mentored career development proposal details a translational research training program in biomarker discovery and clinical study implementation with a goal of identifying metabolite predictors of diabetes and preventive treatment effect. Candidate: The applicant is a recently appointed Endocrinology faculty member at Beth Israel Deaconess Medical Center with a long-term goal to become a physician-scientist who investigates metabolic pathways involved in T2D development and progression. She has 2.5 years of experience in molecular profiling in large human studies and the outlined proposal builds on this background to provide new domains of expertise including prediction modeling, genetics, and clinical study design. Training: The applicant’s development will occur through a blend of laboratory training, didactic courses (including an ongoing MPH), and scientific conferences. The candidate’s mentor is a recognized leader in molecular profiling, integrative “omics”, and cardiometabolic diseases. Her co-mentor is a leader in T2D genetics, and the members of her advisory committee have a distinguished mentoring record and vast expertise in T2D, non-targeted metabolomics, statistical modeling, and clinical trials. Research: Recently, the applicant identified unique metabolite profiles associated with T2D in a large, randomized control trial that compared lifestyle changes and metformin therapy for T2D prevention in individuals with impaired glucose regulation. These associations, including specific phosphatidylcholines and cholesterol esters, remained after adjustments for traditional clinical risk factors suggesting they could serve as predictors of T2D. Furthermore, these metabolites were associated with different rates of T2D progression after lifestyle or metformin treatment and may help guide T2D prevention decisions. The applicant proposes to further extend these findings by (Aim 1) creating metabolite multi-marker prediction models to assess the ability of these metabolites to prospectively predict diabetes development, (Aim 2A) integrate these findings with genetics to uncover metabolic pathways that underly these associations and if they cause diabetes, (Aim 2B) leverage genetics to also identify completely novel circulating small molecules associated with T2D, and (Aim 3) conduct a small prospective cohort study to externally validate these metabolites as predictive biomarkers in a real-world clinical setting. This work will lay the foundation for an NIH R01 application for a clinical trial to assess the predictive utility of metabolite biomarkers for diabetes prevention and transition the candidate to research independence.

项目概要/摘要 背景：2 型糖尿病 (T2D) 的发病率和患病率不断上升，可以通过以下方法缓解： 通过行为改变或药物治疗对高危个体进行成功预防。 确定特定个体患糖尿病的风险以及哪种预防性治疗最有效， 然而，这仍然是一个临床困境。代谢生物标志物代表了解决这些问题的一种新方法 临床挑战，还可能揭示疾病发展的机制。这五年的辅导生涯 开发提案详细介绍了生物标志物发现和临床方面的转化研究培训计划 研究实施的目的是确定糖尿病的代谢预测因子和预防性治疗 影响。候选人： 申请人是贝斯以色列最近任命的内分泌学教员 女执事医疗中心的长期目标是成为研究代谢的医师科学家 参与 T2D 发生和进展的途径。她在分子领域拥有2.5年的经验 大型人类研究中的剖析和概述的提案建立在这一背景之上，以提供新的领域 专业知识包括预测模型、遗传学和临床研究设计。培训：申请人的 发展将通过实验室培训、教学课程（包括正在进行的 MPH）、 和科学会议。候选人的导师是分子分析、综合分析领域公认的领导者 “组学”和心脏代谢疾病。她的共同导师是 T2D 遗传学领域的领导者，她的成员 咨询委员会在 T2D、非靶向领域拥有杰出的指导记录和丰富的专业知识 代谢组学、统计模型和临床试验。研究：最近，申请人发现了独特的 一项大型随机对照试验中与 T2D 相关的代谢特征比较了生活方式的改变和 二甲双胍疗法可用于血糖调节受损个体的 T2D 预防。这些协会， 包括特定的磷脂酰胆碱和胆固醇酯，在传统的调整后仍然保留 临床危险因素表明它们可以作为 T2D 的预测因子。此外，这些代谢物 与生活方式或二甲双胍治疗后不同的 T2D 进展率相关，可能有助于指导 T2D 预防决策。申请人建议通过（目标 1）创建来进一步扩展这些发现 代谢物多标记预测模型，用于评估这些代谢物前瞻性预测的能力 糖尿病的发展，（目标 2A）将这些发现与遗传学相结合，以揭示代谢途径 在这些关联的基础上，如果它们导致糖尿病，（目标 2B）利用遗传学来完全识别 与 T2D 相关的新型循环小分子，并且（目标 3）进行一项小型前瞻性队列研究 在现实世界的临床环境中从外部验证这些代谢物作为预测生物标志物。这项工作将奠定 为 NIH R01 临床试验申请奠定基础，以评估代谢物的预测效用 预防糖尿病的生物标志物并将候选人转变为研究独立性。