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

描述（由申请人提供）：青少年2型糖尿病（T2 D）的增加具有显著的卫生保健后果，因为它与心血管疾病（CVD）的过早发作密切相关。T2 D青年的常见发现包括脂蛋白异常，这些异常随着时间的推移迅速恶化，并可能导致CVD风险增加。由于高密度脂蛋白胆固醇（HDL-C）浓度长期以来与CVD保护有关，最近旨在降低CVD风险的治疗集中在提高HDL-C。不幸的是，使用这些药物的药物试验无法降低CVD风险，尽管HDL-C增加了约70%。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-并且可能起作用，并且不加选择地提高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，我们的初步研究表明，在患有T2 D的青少年中，存在特定人群的大载脂蛋白E（apoE）富集HDL颗粒的耗竭，并且缺乏这些HDL颗粒与临床前CVD（通过脉搏波速度测量的动脉僵硬度）增加相关。该提案的科学目标是确定T2 D是什么原因导致这些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T2 D中特定HDL亚种的组成和功能的改变与临床前CVD的风险增加相关。其基本原理是，改变HDL亚种和CVD风险之间的既定联系将为药理学操作开辟新的途径，以减少高危青年的CVD负担。本K23的目标1将侧重于分离肥胖、胰岛素抵抗和高血糖的影响，以通过利用辛辛那提儿童医院独特的大量精选患者队列，确定导致青少年HDL亚种改变的风险因素。横断面研究将集中于胰岛素抵抗、体重增加和高血糖对HDL亚型的单独和组合的影响，而纵向时程研究将集中于手术减肥后的逆转。在目的2中，我们将探索T2 D介导的富含apoE的大HDL亚种的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，并比较健康和T2 D青少年富含apoE的大HDL颗粒抑制动脉粥样硬化发展中关键步骤的能力：低密度脂蛋白（LDL）颗粒的氧化和防止LDL与蛋白聚糖结合的能力。在目标3中，我们将探讨改变HDL亚类对HDL两个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产生的能力。然后将这些HDL亚种功能与临床前CVD的非侵入性测量相关，以确定T2 D青少年中HDL功能改变的CVD后果。伴随着这个K23的培训目标将开发申请人成为一个独立的，翻译脂质研究人员专注于脂蛋白有助于CVD的机制。培训计划侧重于六个关键领域：1）脂质代谢的直接实验室经验; 2）教学课程; 3）临床中的患者互动; 4）撰写手稿和赠款; 5）领导力培训; 6）与该领域的导师和领导者互动。K23职业发展奖的结果将：i）鉴定HDL组成、功能和血管壁病理学联系之间的相互关系，其远远超出HDL-C与CVD结果的简单相关性，以及iii）为申请人提供脂质代谢方面的全面培训经验，以提交竞争性R 01申请，重点关注改善高危青年心脏保护的疗法。

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.