Understanding the Role of HDL Subspecies in Adolescents with Type 2 Diabetes

了解 HDL 亚种在 2 型糖尿病青少年中的作用

• 批准号: 9032519
• 负责人: AMY SANGHAVI SHAH
• 金额: $ 19.14万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032519
• 关键词: Accounting; Adolescent; Adolescent and Young Adult; Adult; Affect; Apolipoprotein E; Area; Arteries; Atherosclerosis; Attenuated; Basic Science; Body Weight decreased; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Clinic; Clinical; Clinical Research; Complement; Cross-Sectional Studies; Development; Diabetes Mellitus; Disease Outcome; Endothelial Cells; Framingham Heart Study; Gel Chromatography; Goals; Grant; Health; Healthcare; Heterogeneity; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hyperglycemia; Incidence; Insulin Resistance; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leadership; Life; Lipids; Lipoprotein Binding; Lipoproteins; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Manuscripts; Measures; Mediating; Mentors; Metabolism; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathology; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Physiologic pulse; Physiology; Population; Positioning Attribute; Prevalence; Process; Production; Property; Proteins; Proteoglycan; Public Health; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; Scientist; Therapeutic; Time; Training; Vascular Diseases; Weight Gain; Work; Writing; Youth; arterial stiffness; atheroprotective; burden of illness; cardiovascular disorder prevention; cardiovascular disorder risk; career; career development; cohort; early onset; experience; heparin proteoglycan; high risk; improved; insight; laboratory experience; lipid metabolism; macrophage; particle; pre-clinical; premature; prevent; programs; research study; therapy development; trend

DESCRIPTION (provided by applicant): The rise in adolescent type 2 diabetes (T2D) has significant health care consequences as it is strongly associated with a premature onset of cardiovascular disease (CVD). Common findings in T2D youth include lipoprotein abnormalities that worsen rapidly over time and likely contribute to this increased CVD risk. Because high density lipoprotein cholesterol (HDL-C) concentrations have long been associated with CVD protection, recent therapies aimed at lowering CVD risk have focused on raising HDL-C. Unfortunately, drugs trials using these agents have been unable to reduce CVD risk despite increasing HDL-C by some 70%. This is likely because "HDL-C" actually reflects a conglomeration of distinct particles that vary widely in size and protein composition - and presumably function and raising HDL-C indiscriminately does not account for this particle heterogeneity. Work from our laboratory is consistent with this. In fact, our preliminary work has shown that in adolescents with T2D, there is a depletion of a specific population of large apolipoprotein E (apoE) enriched HDL particles and that lack of these HDL particles is associated with an increase in preclinical CVD (arterial stiffness as measured by pulse wave velocity). The scientific goal of this proposal is to determine what it is about T2D that is responsible for these HDL subspecies changes and establish the functional implications of these HDL subspecies changes on CVD development. Our hypothesis is that alteration in the composition and function of specific HDL subspecies in T2D is associated with increased risk of pre-clinical CVD. The rationale is that an established connection between altered HDL subspecies and the risk for CVD will open new avenues for pharmacological manipulation to reduce the CVD burden in high risk youth. Aim 1 of this K23 will focus on isolating the effects of obesity, insulin resistance and hyperglycemia to determine the risk factors that contribute to altered HDL subspecies in adolescents by leveraging a wealth of highly selected patient cohorts uniquely available at Cincinnati Children's Hospital. Cross sectional studies will focus on the impact of insulin resistance, weight gain and hyperglycemia, on HDL subspecies individually and in combination, while longitudinal time course studies will focus on their reversal after surgical weight loss. In Aim 2, we will explore the mechanism(s) by which T2D-mediated depletion of large apoE rich HDL subspecies may result in vascular dysfunction. We will utilize gel filtration chromatography to isolate HDL subspecies and compare the ability of large apoE rich HDL particles from healthy and T2D adolescents to inhibit key steps in the development of atherosclerosis: oxidation of low density lipoprotein (LDL) particles and the ability to prevent LDL binding to proteoglycans. In Aim 3, we will explore the consequences of altered HDL subspecies on two of HDL best known cardioprotective functions: cholesterol efflux and the ability to stimulate nitric oxide production. These HDL subspecies functions will then be related to noninvasive measures of preclinical CVD to establish the CVD consequences of altered HDL function in T2D adolescents. The training goals that accompany this K23 will develop the applicant into an independent, translational lipid researcher focused on the mechanisms by which lipoproteins contribute to CVD. The training plan focuses on six keys areas: 1) a direct laboratory experience in lipid metabolism; 2) didactic coursework; 3) patient interactions in the clinic; 4) writing manuscripts and grants; 5) leadership training; and 6) interacting with mentors and leaders in the field. The outcomes of this K23 career development award will: i) identify the inter-relationships between HDL composition, function and vessel wall pathology connections that go well beyond simple correlations of HDL- C with CVD outcomes, ii) determine how T2D affects lipoprotein metabolism, potentially offering new avenues for therapeutic manipulation, and iii) provide the applicant with a comprehensive training experience in lipid metabolism positioned to submit a competitive R01 application focused on therapies to improve cardio- protection in high risk youth.

描述（由申请人提供）：青少年 2 型糖尿病 (T2D) 的增加具有重大的医疗保健后果，因为它与心血管疾病 (CVD) 的过早发病密切相关。 T2D 青少年的常见发现包括脂蛋白异常，随着时间的推移，脂蛋白异常会迅速恶化，并可能导致 CVD 风险增加。由于高密度脂蛋白胆固醇 (HDL-C) 浓度长期以来一直与 CVD 保护相关，因此最近旨在降低 CVD 风险的治疗方法主要集中在提高 HDL-C 上。不幸的是，尽管 HDL-C 增加了约 70%，但使用这些药物的药物试验仍无法降低 CVD 风险。这可能是因为“HDL-C”实际上反映了不同颗粒的聚集，这些颗粒的大小和蛋白质组成差异很大，并且可能发挥作用，并且不加区别地提高 HDL-C 并不能解释这种颗粒异质性。我们实验室的工作与此一致。事实上，我们的初步工作表明，在患有 T2D 的青少年中，特定人群中富含大载脂蛋白 E (apoE) 的 HDL 颗粒有所减少，而这些 HDL 颗粒的缺乏与临床前 CVD（动脉硬化）的增加有关。通过脉搏波速度测量）。该提案的科学目标是确定 T2D 的哪些因素导致这些 HDL 亚种变化，并确定这些 HDL 亚种变化对 CVD 发展的功能影响。我们的假设是，T2D 中特定 HDL 亚种的组成和功能的改变与临床前 CVD 风险增加相关。其基本原理是，改变的 HDL 亚种与 CVD 风险之间已建立的联系将为药物操作开辟新途径，以减少高危青少年的 CVD 负担。 K23 的目标 1 将重点关注隔离肥胖、胰岛素抵抗和高血糖的影响，通过利用辛辛那提儿童医院独有的大量精心挑选的患者队列，确定导致青少年 HDL 亚种改变的风险因素。横断面研究将重点关注胰岛素抵抗、体重增加和高血糖对 HDL 亚种单独和组合的影响，而纵向时间过程研究将重点关注手术减肥后这些因素的逆转。在目标 2 中，我们将探讨 T2D 介导的富含 apoE 的大 HDL 亚种耗竭可能导致血管功能障碍的机制。我们将利用凝胶过滤色谱分离 HDL 亚种，并比较来自健康和 T2D 青少年的富含 apoE 的大 HDL 颗粒抑制动脉粥样硬化发展的关键步骤的能力：低密度脂蛋白 (LDL) 颗粒的氧化和预防 LDL 的能力与蛋白聚糖结合。在目标 3 中，我们将探讨改变 HDL 亚种对 HDL 两种最著名的心脏保护功能的影响：胆固醇流出和刺激一氧化氮生成的能力。然后将这些 HDL 亚种功能与临床前 CVD 的无创测量相关联，以确定 T2D 青少年 HDL 功能改变的 CVD 后果。 K23 附带的培训目标将把申请人培养成为一名独立的转化型脂质研究人员，专注于脂蛋白导致 CVD 的机制。培训计划重点关注六个关键领域：1）脂质代谢的直接实验室经验； 2）教学课程； 3）患者在诊所的互动； 4）撰写稿件和补助金； 5）领导力培训； 6）与该领域的导师和领导者互动。该 K23 职业发展奖的成果将：i) 确定 HDL 组成、功能和血管壁病理联系之间的相互关系，远远超出 HDL-C 与 CVD 结果的简单相关性，ii) 确定 T2D 如何影响脂蛋白代谢，可能为治疗操作提供新途径，以及 iii) 为申请人提供脂质代谢方面的全面培训经验，以便提交一份竞争性 R01 申请，重点关注改善高危青少年心脏保护的治疗方法。