P-GLYCOPROTEIN EXPRESSION AND FUNCTION IN HIV+ WOMEN

HIV 女性中 P-糖蛋白的表达和功能

• 批准号: 6579420
• 负责人: LESLIE Z BENET
• 金额: $ 20.59万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579420
• 关键词: HIV infections; P glycoprotein; adult human (21+); age difference; antiAIDS agent; cytochrome P450; female; flow cytometry; fluorescent dye /probe; gene expression; hormone regulation /control mechanism; human immunodeficiency virus; human subject; lymphocyte; menopause; multidrug resistance; ovulation; patient oriented research; pharmacokinetics; protease inhibitor; protein localization; protein structure function; racial /ethnic difference; sex hormones; tissue /cell culture; women's health

Description (Abstract Provided by Applicant): We hypothesize that gender, ovulatory function and disease may affect P-glycoprotein (P-gp) expression in the intestine and other organs such as the liver, endometrium and lymphocytes, thereby modulating the effectiveness of protease inhibitors (PIs) in HIV+ women. P-gp expression and function varies with ovulatory function and phase. The highest levels occur during menopause and in the midluteal phase of the cycle; the severity of disease can also influence P-gp activity in various tissues in women (liver, gut, lymphocytes and endometrium). This in turn can affect the pharmacokinetics and pharmacodynamics of protease inhibitors (PIs) as well as the progression of HIV disease. While differences in pharmacokinetics of drugs that are cytochrome P4503A (CYP3A) and P-gp substrates, such as the PIs, are manifested as differences in metabolism, we believe that this end result is regulated by differences in P-gp function and activity rather than by differences in CYP3A expression across the population. Project IV has five specific aims: I) to determine if the intestine, like the liver and endometrium, exhibits variable levels of transporter and enzyme that are regulated by progestins and/or estrogen, (which will also serve as a measure as to how well commonly used cell lines, e.g., liver and endometrium, exhibit characteristics that may be useful in testing the hypothesis); 2) to learn whether an assay in lymphocytes might be used as a simple model for what occurs in the endometrium, intestine and liver; 3) to test whether known differences in P-gp between premenopausal and postmenopausal women translate into differences in PI drug levels; 4) to correlate ovulatory cycle phase (early follicular, midluteal and postmenopausal) and/or P1 levels with markers of viral resistance; and 5) to determine the effects of four parameters: (a) stage of ovulatory cycle phase (early follicular. midluteal or postmenopausal), (b) ethnicity (particularly African American vs. Caucasian), (c) presence vs. absence of HIV infection, and (d) CD4 count strata on P-gp expression, as measured by quantitative analysis of P-gp in tissue biopsies (intestinal cells, endometrium and peripheral blood mononuclear cells) and P-gp function, as measured by PT pharmacokinetic profiles.

描述（申请人提供的摘要）：我们假设该性别， 排卵功能和疾病可能影响P-糖蛋白（P-GP）表达 肠道和其他器官，例如肝脏，子宫内膜和淋巴细胞， 从而调节蛋白酶抑制剂（PI）在HIV+中的有效性 女性。 P-gp的表达和功能随排卵功能和相变而变化。 最高水平发生在更年期和丹特阶段 循环;疾病的严重程度也会影响各种P-gp活性 女性组织（肝，肠道，淋巴细胞和子宫内膜）。 反过来，这会影响蛋白酶的药代动力学和药效学 抑制剂（PI）以及HIV疾病的进展。而差异 在细胞色素P4503A（CYP3A）和P-gp的药物的药代动力学中 诸如PI等底物表现为代谢的差异，我们 认为该最终结果受P-gp功能的差异和 活性而不是在人群中CYP3A表达的差异。 IV项目具有五个具体目标：i）确定肠道是否像 肝脏和子宫内膜表现出可变水平的转运蛋白和酶 由孕激素和/或雌激素调节（这也将作为一个 测量常用细胞系的含量，例如肝脏和子宫内膜， 展示特征可能有助于检验假设）； 2）到 了解是否可以将淋巴细胞中的测定用作简单的模型 发生在子宫内膜，肠道和肝脏中； 3）测试是否已知 绝经前和绝经后妇女之间P-gp的差异翻译 在PI药物水平上差异； 4）将排卵循环阶段相关 （早期卵泡，中肠和绝经后）和/或P1水平，带有标记 病毒抗性； 5）确定四个参数的影响：（a） 排卵循环阶段（早期卵泡。 绝经后），（b）种族（特别是非裔美国人与高加索人）， （c）存在与不存在HIV感染的存在，以及（d）P-gp上的CD4计数层 表达，通过对组织活检中P-gp的定量分析来衡量 （肠细胞，子宫内膜和外周血单核细胞）和 P-gp功能，通过PT药代动力学谱测量。