ADIPOCYTE TURNOVER AND METABOLISM IN HIV-1 LIPOATROPHY

描述(改编自申请人的摘要) 皮下脂肪的丢失或脂肪萎缩(LA)，是一个重要但不好的 了解HIV-1感染患者的问题。近期临床研究 提示存在两种与抗逆转录病毒(ARV)相关的LA综合征 治疗：蛋白酶抑制剂(PI)相关和核苷逆转录- TASE抑制剂(NRTI)相关。脂肪流失的本质(脂肪细胞减少 每个脂肪细胞的数量或脂肪含量)及其潜在的代谢/动力学 基础(脂肪细胞的破坏或再生减少，改变 前脂肪细胞池大小或分化，和/或脂肪细胞的变化 脂肪生成或脂肪分解)仍不清楚。脂肪细胞是否发生周转 在正常人体生理学或LA综合征中尚未确定。这个 这些研究的主要目的是了解脂肪细胞的作用 洛杉矶的周转(增殖、前脂肪细胞分化和死亡) 综合症。第二个目标是在脂肪组织之间建立联系 中间代谢中的动力学或质量和变化。现在是时候了 有可能直接在人类体内测量细胞增殖，通过标记 分裂细胞中DNA的脱氧核糖部分，带有2H-葡萄糖。这项技术 已经为长期研究慢周转细胞而进行了修改，例如 脂肪细胞，通过给药2H2O。在人类受试者中进行的初步研究 已证实成熟脂肪细胞和基质血管细胞的增殖 脂肪组织。脂肪组织动力学的横断面研究将是 在健康的HIV-1感染者(n=12)或与NRTI相关的人(n=12)中实施 综合症。一项纵向研究也将在两个月前和期间进行 以PI-(n=18)为基础的ARV治疗多年，以建立时间进程， 脂肪组织改变的频率及相关因素。扩散和池塘 前脂肪细胞的大小将由前脂肪细胞因子-1来确定 (首选-1)。肝脏胰岛素抵抗和极低密度脂蛋白-甘油三酯代谢 同时测量的。总之，了解脂肪组织的必要性 人类抗逆转录病毒前体脂肪细胞周转的动力学。基础和临床 关于脂肪组织周转和功能的重要问题 以提高对自然历史、可逆性、 急性呼吸道合胞病毒相关性肺炎的临床分类和潜在治疗策略 洛杉矶。

DESCRIPTION (Adapted from the applicant's abstract) The loss of subcutaneous fat or lipoatrophy (LA), is an important but poorly understood problem in HIV-1 infected patients. Recent clinical studies suggest the existence of two LA syndromes associated with antiretroviral (ARV) therapy: protease inhibitor (PI)-associated and nucleoside reverse transcrip- tase inhibitor (NRTI)-associated. The nature of fat loss (reduced adipocyte number or lipid content per fat cell) and its underlying metabolic/kinetic basis (destruction or reduced regeneration of fat cells, changes in preadipocyte pool size or differentiation, and/or changes in adipocyte lipogenesis or lipolysis) remain unknown. Whether adipocyte turnover occurs in normal human physiology or LA syndromes has not been determined. The primary objective of these studies is to understand the role of adipocyte turnover (proliferation, differentiation from preadipocytes, and death) in LA syndromes. A second goal is to establish connections between adipose tissue kinetics or mass and alterations in intermediary metabolism. It is now possible to measure cell proliferation directly in humans, by labeling the deoxyribose moiety of DNA in dividing cells, with 2H-glucose. This technique has been modified for long-term studies of slow turnover cells, such as adipocytes, by administration of 2H2O. Pilot studies in human subjects have confirmed proliferation in mature adipocytes and stromal-vascular cells from adipose tissue. Cross-sectional studies of adipose tissue kinetics will be performed in health HIV-1 infected persons (n=12) or NRTI-associated (n=12) syndromes. A longitudinal study will also be performed before and during two years of ARV therapy with PI-(n=18) based regimens, to establish time course, frequency and correlates of adipose tissue changes. Proliferation and pool size of preadipocytes will be determined by use of preadipocyte factor-1 (pref-1). Hepatic insulin resistance and VLDL-triglyceride metabolism will be measured concurrently. In summary, the need to understand adipose tissue kinetics in ARV-preadipocyte turnover in humans. Basic and clinically important questions concerning the turnover and function of adipose tissue can be addressed, to improve understanding of natural history, reversibility, clinical classification and potential treatment strategies for ARV-associated LA.