Apoptotic Gene Regulation in Hypoxic Renal Pathology

缺氧肾脏病理学中的凋亡基因调控

• 批准号: 6619629
• 负责人: Zheng Dong
• 金额: $ 21.45万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619629
• 关键词: biological signal transduction; cell death; cellular pathology; cysteine endopeptidases; enzyme activity; gel mobility shift assay; genetic regulation; genetic transcription; immunoprecipitation; kidney disorder; messenger RNA; mitogen activated protein kinase; nuclear runoff assay; point mutation; protein kinase; renal ischemia /hypoxia; reporter genes; transcription factor

Hypoxia plays a fundamental role in many pathogenic processes. Cancer cells in solid tumors adapt to the hypoxic microenvironment and become death-resistant and highly metastatic. On the other hand, hypoxia leads to cell death and is a key determinant of tissue pathology in ischemic diseases including myocardial infaraction, stroke and acute renal failure. Our long-term goal is to understand why some cells die during hypoxia and others can adapt to the stress and survive. One of the key factors that determine the fate of hypoxic cells appears to be gene expression. While it has been shown that mammalian cells express gene (products to increase oxygen delivery and facilitate metabolic adaptation to hypoxia, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. The objective of this proposal is to examine hypoxic regulation of genes that participate in or regulate apoptotic cell death in kidney epithelium. Our hypothesis is that expression of apoptotic genes is regulated by hypoxia. Balance between the pro- and anti- apoptotic genes is crucial for cell homeostasis and plays an essential role in determining death or survival of hypoxic cells. This hypothesis is formulated based on strong preliminary findings showing hypoxic regulation of death promoting as well as death inhibitory genes. We will test the hypothesis by pursuing four specific aims: 1, examine the roles played by transcription, mRNA stabilization and protein turnover in hypoxic expression of apoptotic genes; 2, dissect the signaling pathways that mediate apoptotic gene expression under hypoxia; 3, delineate the transcriptional mechanisms responsible for hypoxic apoptotic gene expression; 4, determine the roles played by the up-regulated apoptotic genes in cell injury or adaptation during in vitro hypoxia and in vivo ischemia. The proposed research is among the first to investigate hypoxic regulation of cell death related genes and determine its role in ischemic tissue pathology. The studies will yield important information on apoptotic gene regulation. Moreover, new insights into hypoxic cell injury and adaptation are expected. Finally, completion of these studies may help design genetic and pharmacologic strategies to diminish hypoxic tissue pathology attributable to apoptotic cell death.

缺氧在许多致病过程中起着重要作用。 实体瘤中的癌细胞适应低氧微环境，并变得耐死亡和高转移性。 另一方面，缺氧导致细胞死亡，并且是缺血性疾病（包括心肌梗死、中风和急性肾衰竭）中的组织病理学的关键决定因素。我们的长期目标是了解为什么一些细胞在缺氧时死亡，而另一些细胞可以适应压力并存活下来。决定低氧细胞命运的关键因素之一似乎是基因表达。 虽然已经表明哺乳动物细胞表达基因产物以增加氧递送并促进对缺氧的代谢适应，但是关于直接参与细胞死亡或死亡抗性的基因的缺氧调节知之甚少。 这个建议的目的是研究参与或调节肾上皮细胞凋亡的基因的缺氧调节。 我们的假设是，凋亡基因的表达是由缺氧调节。 促凋亡基因和抗凋亡基因之间的平衡对于细胞内稳态至关重要，并且在决定缺氧细胞的死亡或存活中起重要作用。这一假设是基于强有力的初步研究结果，表明缺氧调节死亡促进以及死亡抑制基因。 我们将通过以下四个具体目标来验证这一假说：1、研究转录、mRNA稳定性和蛋白质周转在缺氧条件下凋亡基因表达中的作用; 2、剖析缺氧条件下介导凋亡基因表达的信号通路; 3、阐明缺氧条件下凋亡基因表达的转录机制; 4.确定上调的凋亡基因在体外缺氧和体内缺血时细胞损伤或适应中所起的作用。 这项研究是首次研究细胞死亡相关基因的缺氧调节，并确定其在缺血性组织病理学中的作用。 这些研究将为细胞凋亡基因调控提供重要信息。 此外，新的见解缺氧细胞损伤和适应的预期。 最后，这些研究的完成可能有助于设计遗传和药理学策略，以减少缺氧组织病理归因于凋亡细胞死亡。