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: 9235149
• 负责人: AMY SANGHAVI SHAH
• 金额: $ 19.04万
• 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/9235149
• 关键词: 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; Healthcare; Heterogeneity; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hyperglycemia; Incidence; Individual; 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; Pharmacology; Physiologic pulse; Physiology; Population; Positioning Attribute; Prevalence; Process; Production; Property; Proteins; Proteoglycan; Public Health; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; Scientist; Supervision; Therapeutic; Thinness; 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; experimental study; heparin proteoglycan; high risk; improved; insight; laboratory experience; lipid metabolism; macrophage; particle; pre-clinical; premature; prevent; programs; public health relevance; 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）的过早发作密切相关。 T2D青年的常见发现包括随着时间的流逝迅速恶化的脂蛋白异常，并可能导致CVD风险增加。由于高密度脂蛋白胆固醇（HDL-C）的浓度长期与CVD保护有关，因此旨在降低CVD风险的近期疗法集中于提高HDL-C。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”实际上反映了不同大小和蛋白质组成差异很大的不同颗粒的集团 - 并且大概起作用并促进HDL-C不加选择地提高了这种粒子异质性。我们实验室的工作与此一致。实际上，我们的初步工作表明，在具有T2D的青少年中，特定的大量载脂蛋白E（APOE）富集的HDL颗粒的耗竭，并且缺乏这些HDL颗粒的缺乏与旋链型CVD相关（随着脉搏波Velocity的测量动脉刚度的增加）。该提案的科学目标是确定造成这些HDL亚种的变化的T2D的含义，并确定这些HDL亚种对CVD开发的变化的功能含义。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的风险增加有关。理由是，改变的HDL亚种与CVD风险之间建立的联系将为药理学操纵提供新的途径，以减轻高风险青年的CVD负担。本k23的目标1将集中于隔离肥胖，胰岛素抵抗和高血糖的影响，以确定危险因素通过利用辛辛那提儿童医院独特可用的大量高度选择的患者群体，从而导致青少年HDL亚种的改变。横截面研究将重点介绍胰岛素抵抗，体重增加和高血症的影响，对HDL亚种的单独和结合，而纵向时间课程研究将集中在手术体重减轻后的逆转上。在AIM 2中，我们将探讨T2D介导的大型APOE HDL亚种的T2D介导的耗竭的机制可能导致血管功能障碍。我们将利用凝胶过滤色谱法分离HDL亚种，并比较大型APOE丰富的HDL颗粒从健康和T2D青少年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（LDL）颗粒的氧化能力以及预防LDL与蛋白酶结合的能力。在AIM 3中，我们将探讨HDL亚种改变的后果对HDL两个最著名的心脏保护功能：胆固醇外排和刺激一氧化氮产生的能力。然后，这些HDL亚种功能将与临床前CVD的无创测量有关，以确定T2D青少年中HDL功能改变的CVD后果。伴随该K23的培训目标将把申请人发展为一个独立的转化脂质研究人员，该研究人员着重于脂蛋白对CVD的贡献的机制。培训计划的重点是六个钥匙领域：1）脂质代谢方面的直接实验室经验； 2）教学课程； 3）诊所中的患者相互作用； 4）写手稿和赠款； 5）领导培训； 6）与该领域的导师和领导人互动。该K23职业发展奖的结果将：i）确定HDL组成，功能和船舶墙壁病理学连接之间的相互关系远远超出了HDL-C与CVD结果的简单相关性，ii）ii）确定T2D如何影响脂蛋白代谢，以提供新的培训，以提供适用于新的途径，以提供新的型号，并提供III II III次，并且III III II III次，并且III）适用于III）。代谢定位，提交有竞争力的R01申请，该应用程序旨在改善高风险青年的心脏保护。