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: 6370183
• 负责人: Zheng Dong
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6370183
• 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.

低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，并变得耐死亡和高度转移。另一方面，缺氧导致细胞死亡，是心肌梗死、中风和急性肾功能衰竭等缺血性疾病组织病理的关键决定因素。我们的长期目标是了解为什么一些细胞在缺氧期间死亡，而另一些细胞能够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。虽然已经证明哺乳动物细胞表达增加氧气输送和促进新陈代谢适应低氧的基因(产物)，但对直接参与细胞死亡或死亡抵抗的基因的低氧调节知之甚少。这项建议的目的是研究参与或调节肾上皮细胞凋亡的基因的低氧调节。我们的假设是，凋亡基因的表达受缺氧的调节。促凋亡和抗凋亡基因之间的平衡对细胞内环境的稳定至关重要，在决定低氧细胞的死亡或存活方面起着至关重要的作用。这一假说是基于强有力的初步发现提出的，这些发现表明低氧对死亡促进基因和死亡抑制基因都有调节作用。我们将通过四个特定的目标来验证这一假说：1，检测转录、mRNA稳定和蛋白质周转在缺氧表达凋亡基因中所起的作用；2，剖析在缺氧条件下介导凋亡基因表达的信号通路；3，描述导致缺氧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。这项拟议的研究是第一批研究细胞死亡相关基因的低氧调节并确定其在缺血组织病理学中的作用的研究之一。这些研究将提供有关凋亡基因调控的重要信息。此外，对缺氧细胞损伤和适应的新见解也是可望的。最后，这些研究的完成可能有助于设计遗传和药物策略，以减少可归因于细胞凋亡的缺氧性组织病理。