THE ALTERED PROTEIN METABOLISM OF PEDIATRIC PATIENTS WITH HIV INFECTION

HIV 感染儿科患者蛋白质代谢的改变

• 批准号: 7950648
• 负责人: FAROOK JAHOOR
• 金额: $ 7.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950648
• 关键词: Adolescent; Age; Apoprotein (B); Apoproteins; Appearance; Body Composition; Cardiovascular Diseases; Catabolism; Child; Childhood; Cholesterol; Chronic; Chylomicrons; Clinical; Clinical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; DEXA; Diet; Diet Modification; Dietary Proteins; Dietary Supplementation; Disease; Dyslipidemias; Esterification; Failure; Fasting; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Funding; Gender; Grant; Growth; HIV Infections; Hepatic; High Density Lipoproteins; Highly Active Antiretroviral Therapy; Hydrolysis; Hypertriglyceridemia; Institution; Intake; Kinetics; Lead; Life Expectancy; Lipids; Lipolysis; Liver; Matched Group; Measures; Metabolic; Metabolic Diseases; Mono-S; Morbidity - disease rate; Outcome; Patients; Pharmaceutical Preparations; Plasma; Protein Biosynthesis; Proteins; Relative (related person); Research; Research Personnel; Resources; Secondary to; Source; Staging; Supplementation; Syndrome; Testing; Tracer; Triglycerides; United States National Institutes of Health; Unsaturated Fatty Acids; Up-Regulation; Very low density lipoprotein; apolipoprotein B-100; fatty acid oxidation; feeding; hypercholesterolemia; improved; indexing; lipoprotein lipase; mortality; prepuberty; protein metabolism; research study; reverse cholesterol transport; stable isotope; sterol esterase; young adult

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1a) The hypertriglyceridemia of HIV-infected pediatric patients with the dyslipidemia syndrome is the result of the combined effects of an increased rate of VLDL synthesis, secondary to a faster rate of lipolysis in the fasted state, and impaired hydrolysis of VLDL- and chylomicron-TG, secondary to impaired lipoprotein lipase activity in both the fed and fasted states. 1b) The hypercholesterolemia of HIV-infected patients with dyslipidemia is due to impaired reverse transport of cholesterol to the liver because of a reduction in the availability of HDL-apoA1. 2) Consuming a diet of less fat, comprised primarily of unsaturated fatty acids will ameliorate the hypertriglyceridemia and hypercholesterolemia of patients with the dyslipidemia syndrome. 3) Despite an adequate dietary protein intake, HIV-infected children have a lower LBM due to a deficit in the availability of endogenous protein to support LBM synthesis. This decreased protein availability is secondary to a chronic upregulation of protein catabolism relative to intake. We further propose that this condition can be ameliorated by dietary supplementation with more energy and protein. Specific aim #1. Measure body composition, plasma cholesterol and triacylglycerol (TG) concentrations, plasma fatty acid appearance rate in the fasted and fed states (indices of hormone sensitive lipase and lipoprotein lipase activities), fatty acid oxidation, hepatic fatty acid re-esterification, the concentration and synthesis rates of high density lipoprotein apoprotein A1 (HDL-apoA1), very low density lipoprotein TG and apoprotein B-100 (VLDL-TG and -apoB-100) and lipoprotein lipase activity in a group of HIV-infected adolescents with the dyslipidemia syndrome versus an age, gender, disease stage and drug treatment matched group without dyslipidemia. Specific aim #2. Compare the effects of a reduced fat diet (28% energy) comprised of a greater proportion of mono- and poly-unsaturated fatty acids versus no dietary modification on these same variables in HIV-infected adolescents with dyslipidemia. Specific aim #3. Measure body composition and protein kinetics in prepubertal HIV-infected children versus age and gender matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on protein kinetics in the HIV-infected group of children. Although highly active anti-retroviral therapy (HAART) has markedly reduced the morbidity and mortality of HIV-infected children, the improved life expectancy is associated with a complex set of metabolic disorders in a subset of patients. These disorders include growth failure with lower lean body mass (LBM) and dyslipidemia, a syndrome characterized by hypertriglyceridemia and hypercholesterolemia. Although the clinical features of these metabolic derangements are described, their mechanistic underpinnings are unknown. It is important to delineate these mechanisms in order to establish new therapies for pediatric patients because growth failure will lead to stunting and chronic dyslipidemia may accelerate the progression to cardiovascular disease in adulthood. In this project we plan to test the following hypotheses: 1) the hypertriglyceridemia of HIV-infected patients with dyslipidemia is the result of an increased rate of very low density lipoprotein (VLDL) synthesis, secondary to a faster rate of lipolysis in the fasted state, and impaired hydrolysis of VLDL- and chylomicron-TG, secondary to impaired lipoprotein lipase activity in the fed state, 2) hypercholesterolemia is in part due to impaired cholesterol transport to the liver because of a reduction in the availability of high density lipoprotein apoprotein A1 (HDL-apoA1), 3) a lower fat diet rich in poly and mono-unsaturated fatty acids will improve the hypertriglyceridemia and hypercholesterolemia of HIV-infected dyslipidemic subjects. With respect to protein metabolism we hypothesize that 4) HIV-infected children have a lower LBM due to a deficit in net protein synthesis because of upregulated protein catabolism. To test these hypotheses we propose to conduct stable isotope tracer experiments to achieve the following specific aims: Specific aim #1. Measure body composition by DEXA, plasma lipid profile, plasma fatty acid appearance rate in the fasted and fed states, fatty acid oxidation, hepatic fatty acid re-esterification, the concentration and synthesis rates of HDL-apoA1, VLDL-TG and -apoB-100, and lipoprotein lipase activity in a group of HIV-infected adolescents and young adults with dyslipidemia versus a matched group without dyslipidemia. Specific aim #2. Compare the effects of a reduced fat diet (28% energy) comprised of a greater proportion of mono- and poly-unsaturated fatty acids versus no dietary modification on these same outcome variables in HIV-infected adolescents with dyslipidemia. Specific aim #3. Measure lean body mass (LBM) and protein kinetics in HIV-infected prepubertal children versus age-and gender-matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on LBM and protein kinetics in the HIV-infected group.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 1a) 患有血脂异常综合征的 HIV 感染儿科患者的高甘油三酯血症是 VLDL 合成率增加（继发于禁食状态下脂肪分解速度加快）以及 VLDL- 和乳糜微粒- 水解受损的综合影响的结果。 TG，继发于进食和禁食状态下脂蛋白脂肪酶活性受损。 1b) 患有血脂异常的 HIV 感染者的高胆固醇血症是由于 HDL-apoA1 的可用性减少而导致胆固醇向肝脏的逆向转运受损。 2) 摄入较少脂肪、主要由不饱和脂肪酸组成的饮食将改善血脂异常综合征患者的高甘油三酯血症和高胆固醇血症。 3) 尽管饮食中蛋白质摄入量充足，但由于缺乏支持 LBM 合成的内源蛋白质，HIV 感染儿童的 LBM 较低。 这种蛋白质利用率的下降是由于蛋白质分解代谢相对于摄入量的长期上调所致。 我们进一步建议，可以通过膳食补充更多的能量和蛋白质来改善这种情况。 具体目标#1。 测量身体成分、血浆胆固醇和三酰甘油（TG）浓度、空腹和进食状态下血浆脂肪酸出现率（激素敏感性脂肪酶和脂蛋白脂肪酶活性指数）、脂肪酸氧化、肝脂肪酸再酯化、浓度和高密度脂蛋白脱辅基蛋白 A1 (HDL-apoA1)、极低密度脂蛋白 TG 和脱辅基蛋白 B-100 (VLDL-TG 和-apoB-100）和脂蛋白脂肪酶活性，比较患有血脂异常综合征的 HIV 感染青少年组与年龄、性别、疾病阶段和药物治疗匹配的无血脂异常组。 具体目标#2。 比较由较大比例的单不饱和脂肪酸和多不饱和脂肪酸组成的减脂饮食（28%能量）与不调整饮食对患有血脂异常的艾滋病毒感染青少年的这些相同变量的影响。 具体目标#3。 测量青春期前 HIV 感染儿童与年龄和性别匹配的 HIV 暴露儿童的身体成分和蛋白质动力学，并确定膳食能量和蛋白质补充对 HIV 感染儿童组蛋白质动力学的影响。 尽管高效抗逆转录病毒治疗 (HAART) 显着降低了 HIV 感染儿童的发病率和死亡率，但预期寿命的延长与部分患者出现一系列复杂的代谢紊乱有关。这些疾病包括生长障碍、低瘦体重 (LBM) 和血脂异常（一种以高甘油三酯血症和高胆固醇血症为特征的综合征）。尽管描述了这些代谢紊乱的临床特征，但其机制基础尚不清楚。描述这些机制对于为儿科患者建立新的疗法非常重要，因为生长障碍会导致发育迟缓，而慢性血脂异常可能会加速成年后心血管疾病的进展。在这个项目中，我们计划测试以下假设：1）患有血脂异常的 HIV 感染患者的高甘油三酯血症是极低密度脂蛋白 (VLDL) 合成率增加的结果，继发于禁食状态下脂肪分解速度加快，以及 VLDL- 和乳糜微粒-TG 的水解受损，继发于进食状态下脂蛋白脂肪酶活性受损，2) 高胆固醇血症部分是由于受损由于高密度脂蛋白脱辅基蛋白 A1 (HDL-apoA1) 的可用性减少，胆固醇转运至肝脏，3) 富含多聚和单不饱和脂肪酸的低脂饮食将改善 HIV 感染的血脂异常的高甘油三酯血症和高胆固醇血症科目。 关于蛋白质代谢，我们假设 4) HIV 感染儿童的 LBM 较低，因为蛋白质分解代谢上调导致净蛋白质合成不足。为了检验这些假设，我们建议进行稳定同位素示踪剂实验，以实现以下具体目标：具体目标#1。 通过 DEXA 测量身体成分、血浆脂质谱、空腹和进食状态下的血浆脂肪酸出现率、脂肪酸氧化、肝脂肪酸再酯化、HDL-apoA1、VLDL-TG 和 -apoB- 的浓度和合成率100，以及患有血脂异常的 HIV 感染青少年和年轻人组与没有血脂异常的对照组的脂蛋白脂肪酶活性。 具体目标#2。 比较由较大比例的单不饱和脂肪酸和多不饱和脂肪酸组成的低脂饮食（28%能量）与不调整饮食对患有血脂异常的艾滋病毒感染青少年的这些相同结果变量的影响。 具体目标#3。 测量感染 HIV 的青春期前儿童与年龄和性别匹配的 HIV 暴露儿童的去脂体重 (LBM) 和蛋白质动力学，并确定膳食能量和蛋白质补充对 HIV 感染组的 LBM 和蛋白质动力学的影响。