HNF-4 FUNCTION IN MODELS OF TRAUMATIC INJURY

HNF-4 在创伤模型中的功能

• 批准号: 6999687
• 负责人: PETER A BURKE
• 金额: $ 4.33万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999687
• 关键词: HNF; FUNCTION; MODELS; TRAUMATIC; INJURY

DESCRIPTION (provided by applicant): The body's immediate response to serious trauma, denoted the Acute Phase Response (APR), coordinates a wide variety of inflammatory signals, and produces a common response, in the massive induction of protective proteins by the liver. While APR is designed for survival, severe or prolonged activation of this response can lead to organ failure and death, as its induction is inevitably associated with interruption of normal liver function. Evidence suggests that the APR's repression of steady-state liver function is a byproduct of its mode of induction. Further evidence suggests that this is a highly regulated process which shares an early cell state, and some signals with the proliferative response. Evidence is presented that negative regulation of differentiated genes may be mediated through phosphorylation of a small web of liver-specific transcription factors, particularly HNF-4. Better understanding of this process could potentially have therapeutic importance in allowing more reliable resolution of the acute phase. The first aim is to dissect where HNF-4 phosphorylation occurs, by phosphopeptide mapping, to identify what kinases and thus signal transduction pathways are involved. This will also generate original materials, in the form of altered HNF-4 molecules, to test the importance of this phosphorylation to APR and regeneration. The second aim is to trace the effect of this phosphorylation on the biochemical activities of HNF-4, namely its DNA binding and site selection, and changes in its interactions and activities in the cell, by diagnostic chromatin immunoprecipitation. Third, using DNA microarrays, a global picture of the genes regulated by HNF-4 and its modification will be obtained and compared to that from several acute phase inductions at early stages. This will test both the importance of HNF-4's modification, and establish what transcriptional events are common to the early phase of APR, when normal liver function retracts and the liver prepares for subsequent massive induction.

描述（由申请人提供）： 人体对严重创伤的立即反应，表示急性相反应（APR），协调各种炎症信号，并在肝脏对保护性蛋白的大量诱导中产生共同的反应。尽管APR是为生存而设计的，但这种反应的严重激活或长时间激活可能导致器官衰竭和死亡，因为它的诱导不可避免地与正常肝功能的中断有关。证据表明，APR对稳态肝功能的抑制是其诱导方式的副产品。进一步的证据表明，这是一个高度调节的过程，具有早期的细胞状态，并且有一些具有增殖反应的信号。有证据表明，分化基因的负调节可以通过磷酸化的小肝脏特异性转录因子（尤其是HNF-4）的磷酸化来介导。更好地理解这一过程可能在允许更可靠地解决急性阶段具有治疗意义。第一个目的是通过磷酸肽映射来剖析HNF-4磷酸化发生的位置，以识别涉及哪些激酶，从而涉及信号转导途径。这还将以改变HNF-4分子的形式生成原始材料，以测试这种磷酸化对APR和再生的重要性。第二个目的是追踪这种磷酸化对HNF-4的生化活性的影响，即其DNA结合和位点选择，以及通过诊断染色质免疫沉淀而变化。第三，使用DNA微阵列，将获得由HNF-4调节的基因及其修饰的全局图，并与早期阶段的几种急性相归因进行比较。这将测试HNF-4修饰的重要性，并确定当正常肝功能缩回和肝脏为随后的大规模诱导准备时，APR早期的转录事件与APR的早期相同。