Regulation of Lipotoxicity by the non-coding RNA gadd7

非编码 RNA gadd7 的脂毒性调节

• 批准号: 7294862
• 负责人: Rita Thomas Brookheart
• 金额: $ 2.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-21 至 2008-06-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294862
• 关键词: Adipose tissue; Apoptosis; Cardiomyopathies; Cell Death; Cells; Chinese Hamster Ovary Cell; Condition; Cultured Cells; Disease; Disruption; Endoplasmic Reticulum; Exposure to; Family member; Fatty Acids; Fatty acid glycerol esters; Functional RNA; Functional disorder; Gene Expression; Gene Family; Generations; Genes; Genetic Screening; Heart; Heart failure; Human Development; Hydrogen Peroxide; Metabolic Diseases; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Organ; Oxidative Stress; Palmitates; Palmitic Acids; Pancreas; Pathogenesis; Pathway interactions; Personal Satisfaction; Phenotype; Predisposition; Process; RNA; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Small Interfering RNA; Stress; Supplementation; Testing; biological adaptation to stress; mutant; programs; response; uptake

DESCRIPTION (provided by applicant): Lipotoxicity is the process by which non-adipose tissues, such as the heart and pancreas, accumulate an excess of fatty acids leading to cellular dysfunction and cell death. Lipotoxic-cell death is implicated in the development of human metabolic diseases such as cardiomyopathy and type 2 diabetes. The generation of reactive oxygen species (ROS) and activation of the ER stress response are central to lipotoxic-cell death. However, the exact molecular pathways involved in this process have not been well characterized. To elucidate the key players in the lipotoxic-response, a genetic screen in Chinese hamster ovary cells was carried out by our lab. The screen led to the identification of the non-coding RNA gadd7, which has no known function. Gadd7 expression is induced by the ROS precussor H2O2 and several of its gene family members are associated with the ER stress response. These results and the isolation of gadd7 in our screen suggest a role for gadd7 in the lipotoxic-response. This proposal will test the hypothesis that gadd7 is regulated by lipotoxic-conditions and functions to regulate a program of gene expression in the lipotoxic- response. My aims are to: 1. Confirm the role of gadd7 in lipotoxicity, 2. Characterize the step in the lipotoxic-response where gadd7 disruption inhibits lipotoxic-cell death, 3. Determine the function of gadd7 in the lipotoxic-response by assessing if gadd7 functions as a regulatory RNA. The excess accumulation of fat is implicated in the pathogenesis of diseases like heart failure and type 2 diabetes. The proposed research will increase our understanding of how excess fat disrupts organ function, contributing to the onset of these diseases, and may provide new avenues of treatment and therapy.

描述（由申请人提供）：脂肪毒性是非脂肪组织（例如心脏和胰腺）积累过量的脂肪酸，导致细胞功能障碍和细胞死亡的过程。 Lipotoxic细胞死亡与人类代谢疾病（如心肌病和2型糖尿病）的发展有关。活性氧（ROS）的产生和ER应激反应的激活对于脂肪毒性细胞死亡至关重要。但是，此过程中涉及的确切分子途径尚未得到很好的表征。为了阐明脂肪毒性反应中的关键参与者，我们的实验室进行了中国仓鼠卵巢细胞的遗传筛查。屏幕导致识别非编码RNA GADD7，该RNA GADD7没有已知功能。 GADD7的表达是由ROS precuseor H2O2诱导的，其几个基因家族成员与ER应力反应有关。这些结果和在我们屏幕上的GADD7的分离表明GADD7在脂肪毒性反应中的作用。该建议将检验以下假设：GADD7受脂肪毒性条件和功能调节，以调节脂肪毒性反应中基因表达程序。我的目的是：1。确认GADD7在脂肪毒性中的作用，2。表征Lipototoxic-Response的一步，其中GADD7破坏抑制脂肪毒性细胞死亡，3。确定GADD7在lipototototoxic-Response中的功能，通过评估GADD7在lipototoxic-Respons中的功能。脂肪的过量积累与心力衰竭和2型糖尿病等疾病的发病机理有关。拟议的研究将增加我们对多余脂肪如何破坏器官功能的理解，从而导致这些疾病的发作，并可能提供新的治疗和治疗途径。