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: 10617338
• 负责人: Zsu-Zsu Chen
• 金额: $ 16.47万
• 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/10617338
• 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; Pharmacotherapy; Phenotype; Phospholipids; Physicians; Pilot Projects; Plasma; Population; Prediabetes syndrome; Prediction of Response to Therapy; Prevalence; Prevention; Preventive treatment; Prospective, cohort study; Randomized; Randomized, Controlled Trials; 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; biomarker discovery; blood glucose regulation; burden of illness; career development; clinical biomarkers; clinical decision-making; clinical phenotype; clinical predictive model; clinical risk; cohort; diabetes mellitus genetics; diabetes prevention program; diabetes risk; effective therapy; experience; fasting glucose; fasting plasma glucose; follow-up; functional genomics; genomic locus; high risk; high risk population; impaired glucose tolerance; insight; interest; laboratory experience; member; metabolomics; multiple omics; novel; novel marker; novel strategies; pharmacologic; population based; predictive marker; predictive modeling; prevent; preventive intervention; prospective; randomized, controlled study; 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.

项目摘要/摘要 背景：2型糖尿病（T2D）的发病率和患病率增加。 在处于高风险的个体中，成功预防行为改变或药物治疗。 确定特定人的糖尿病风险，哪种预防治疗将是最有效的， 但是，仍然是临床困境。代谢物生物标志物代表了一种解决这些问题的新方法 临床挑战，也可能揭示疾病发展的机制。这个五年的职业 开发建议详细详细介绍了生物标志物发现和临床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物预测因子和预防治疗 影响。候选人：申请人是贝丝以​​色列最近任命的内分泌学院成员 执事医疗中心具有长期目标，以成为一名身体科学家，他研究代谢 参与T2D发展和进展的途径。她有2。5年的分子经验 大型人类研究和概述的提案基于此背景，以提供新的领域 专业知识，包括预测建模，遗传学和临床研究设计。培训：申请人的 开发将通过实验室培训，教学课程（包括持续的MPH）的融合来进行开发， 和科学会议。候选人的心理是分子分析的公认领导者，整合 “ OMICS”和心脏代谢性疾病。她的同事是T2D遗传学的领导者，她的成员 咨询委员会在T2D中具有杰出的心理记录和丰富的专业知识，无目标 代谢组学，统计建模和临床试验。研究：最近，适用的确定的独特 在一项大型，随机的对照试验中，与T2D相关的代谢物概况，该试验比较生活方式的变化和 葡萄糖调节受损的个体中预防T2D的二甲双胍治疗。这些关联， 在调整传统后，包括特定的磷脂酰胆碱和胆固醇酯 临床风险因素表明它们可以作为T2D的预测指标。此外，这些代谢物是 与生活方式或二甲双胍治疗后T2D进展的不同率有关，可能有助于指导 T2D预防决策。申请人提出的提议通过（AIM 1）创建进一步扩展这些发现 代谢产物多标记预测模型评估这些代谢物预测性预测的能力 糖尿病的发育，（目标2a）将这些发现与遗传学融合在一起，以发现代谢途径 这些关联的基础，如果它们引起糖尿病，（AIM 2B）利用遗传学也完全识别 与T2D相关的新型循环小分子，（AIM 3）进行小型前瞻性队列研究 在现实世界中，外部验证这些代谢物为预测生物标志物。这项工作将是 NIH R01申请临床试验的基础，以评估代谢物的预测效用 预防糖尿病和过渡候选人研究独立性的生物标志物。

项目成果

Surface Electrical Impedance Myography Detects Skeletal Muscle Atrophy in Aged Wildtype Zebrafish and Aged gpr27 Knockout Zebrafish.

• DOI: 10.3390/biomedicines11071938
• 发表时间: 2023-07-07
• 期刊: BIOMEDICINES
• 影响因子: 4.7
• 作者: Rutkove, Seward B.;Chen, Zsu-Zsu;Pandeya, Sarbesh;Callegari, Santiago;Mourey, Tyler;Nagy, Janice A.;Nath, Anjali K.
• 通讯作者: Nath, Anjali K.

Understanding Myocardial Metabolism in the Context of Cardio-Oncology.

• DOI: 10.1016/j.hfc.2022.02.004
• 发表时间: 2022-07
• 期刊: Heart failure clinics
• 影响因子: 3.4
• 作者: Jing Liu;Zsu-Zsu Chen-Zsu;Jagvi R. Patel;Aarti H Asnani