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（摘要由申请人提供）：我们假设性别， 排卵功能和疾病可能影响 P-糖蛋白 (P-gp) 的表达 肠道和其他器官，如肝脏、子宫内膜和淋巴细胞， 从而调节蛋白酶抑制剂 (PI) 对 HIV+ 的有效性 女性。 P-gp 的表达和功能随排卵功能和阶段的不同而变化。 最高水平出现在更年期和黄体中期 循环;疾病的严重程度也会影响多种疾病的 P-gp 活性 女性组织（肝脏、肠道、淋巴细胞和子宫内膜）。 这反过来又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。虽然差异 细胞色素 P4503A (CYP3A) 和 P-gp 药物的药代动力学 底物，例如 PI，表现为代谢差异，我们 认为这一最终结果是由 P-gp 功能的差异调节的 活性而不是人群中 CYP3A 表达的差异。 项目 IV 有五个具体目标： I) 确定肠道是否像 肝脏和子宫内膜，表现出不同水平的转运蛋白和酶， 受孕激素和/或雌激素调节，（这也将作为 测量常用细胞系（例如肝脏和子宫内膜）的效果如何， 表现出可能有助于检验假设的特征）； 2）到 了解淋巴细胞测定是否可以用作简单模型 发生于子宫内膜、肠道和肝脏； 3）测试是否已知 绝经前和绝经后女性 P-gp 的差异翻译 PI药物水平的差异； 4) 关联排卵周期阶段 （卵泡早期、黄体中期和绝经后）和/或带有标记的 P1 水平 病毒抵抗力； 5) 确定四个参数的影响：(a) 排卵周期阶段（卵泡早期、黄体中期或 绝经后），（b）种族（特别是非裔美国人与白种人）， (c) 是否存在 HIV 感染，以及 (d) P-gp 上的 CD4 计数层 通过组织活检中 P-gp 的定量分析来测量表达 （肠细胞、子宫内膜和外周血单核细胞）和 P-gp 功能，通过 PT 药代动力学曲线测量。