Epigenetic factors and HIV-associated Nephropathy

表观遗传因素与 HIV 相关肾病

• 批准号: 8845549
• 负责人: PRAVIN C SINGHAL
• 金额: $ 61.8万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845549
• 关键词: AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; African American; Attenuated; Biopsy; Complication; Consequences of HIV; DNA Methylation; Data; Development; Dilatation - action; Down-Regulation; Doxycycline; E-Cadherin; End stage renal failure; Epigenetic Process; Epithelial Cells; Focal Segmental Glomerulosclerosis; Gene Expression; Genes; Genetic Transcription; HIV; HIV Infections; HIV-1; Hospitalization; Individual; Ingestion; Integration Host Factors; Kidney; Laboratories; Lesion; Molecular; Mus; P-Cadherin; Pathogenesis; Patients; Phase; Phenotype; Play; Population; Prevention; Proteins; Regulator Genes; Research; Resolution; Role; Serum; Signal Transduction; Snails; Stream; Testing; Therapeutic; Tubular formation; Up-Regulation; Variant; Vitamin D; Vitamin D3 Receptor; Work; base; chromatin modification; crosslink; kidney cell; nephrin; podocyte; prevent; promoter; public health relevance; receptor; receptor expression; slit diaphragm; vpr Genes

DESCRIPTION (provided by applicant): HIV-associated nephropathy (HIVAN) is an important complication of acquired immunodeficiency syndrome (AIDS).Its manifestation requires presence of specific ancestry (APOL1 gene), environmental (HIV infection), and host factors. Although significant research has been done to identify and to delineate the involved genes to correlate with the ancestry but there has been a limited effort to identify subversive activities o HIV, which might be contributing to specific host factors- increased expression of Snail- required for the display of unique phenotype of renal lesions in HIVAN. In preliminary studies, we found that HIV enhanced renal cell expression of Snail (a repressor of E-cadherin transcriptor, and a promoter of proliferative phenotype). Since Snail has been demonstrated to repress transcription of vitamin D receptor (VDR) and nephrin (a podocyte slit diaphragm protein), it carries a potential to alter renal cell phenotype. HIV is known to modulate gene expression by DNA methylation (epigenetic factors). In our laboratory, we observed that both glomerular and tubular epithelial cells in HIVAN mice displayed enhanced expression of Snail and diminished expression of VDR and nephrin. On the basis of these findings we will test the following hypotheses * HIV alters renal cell gene expression through the induction of epigenetic factors * Renal cortical sections of HIVAN mice as well as HIVAN patients would display enhanced Snail expression and diminished expression of E/P-cadherin, VDR, and nephrin * Inhibition of either HIV-induced epigenetic factors, associated downstream signaling, or both would not only attenuate the development of HIVAN phenotype but will also prevent, retard the progression, and/or cause resolution of HIVAN We suggest that testing of these hypotheses will aid in developing therapeutic strategies to prevent, retard the progression, or cause resolution of HIVAN.

描述（由申请人提供）：与HIV相关的肾病（Hivan）是获得性免疫缺陷综合征（AIDS）的重要并发症。它的表现需要特定祖先（APOL1基因），环境（HIV）（HIV感染）和宿主因素。尽管已经进行了重大研究来识别和描述所涉及的基因与祖先相关，但是在识别HIV的颠覆性活动方面有限的努力，这可能导致特定的宿主因素，以增加蜗牛的表达，以显示HIVAN肾脏病变独特的表型。在初步研究中，我们发现HIV增强了蜗牛的肾细胞表达（E-钙粘蛋白转录器的阻遏物和增殖表型的启动子）。由于已证明蜗牛被证明是抑制维生素D受体（VDR）和肾素（一种足细胞裂片diaphragm蛋白）的转录，因此它具有改变肾细胞表型的潜力。已知HIV通过DNA甲基化（表观遗传因子）调节基因表达。在我们的实验室中，我们观察到Hivan小鼠中的肾小球和肾小管上皮细胞均表现出蜗牛表达增强，并且VDR和肾蛋白的表达降低。根据这些发现，我们将检验以下假设 * HIV通过诱导表观遗传因子来改变肾细胞基因的表达 * Hivan小鼠以及Hivan患者的肾皮质切片将显示出增强的蜗牛表达和E/P-钙粘蛋白，VDR和肾蛋白的表达降低 *抑制艾滋病毒诱导的表观遗传因子，相关的下游信号传导，或两者都不会减弱hivan表型的发展，而且还将阻止，阻碍和/或导致Hivan的分辨率 我们建议对这些假设进行检验将有助于制定治疗策略，以防止，阻碍，延伸或导致Hivan的解决方案。