Regulation of Lipotoxicity by the non-coding RNA gadd7

描述(申请人提供)：脂毒性是非脂肪组织，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。脂毒性细胞死亡与人类代谢性疾病的发展有关，如心肌病和2型糖尿病。活性氧(ROS)的产生和内质网应激反应的激活是脂毒性细胞死亡的中心。然而，参与这一过程的确切分子途径还没有得到很好的表征。为了阐明脂毒反应中的关键分子，本实验室对中国仓鼠卵巢细胞进行了遗传筛查。这一筛选导致了对非编码RNA gadd7的鉴定，该基因没有已知的功能。Gadd7的表达是由ROS前体过氧化氢诱导的，它的几个基因家族成员与内质网应激反应有关。这些结果和Gadd7在我们的屏幕上的分离表明，Gadd7在脂毒反应中发挥了作用。这项提议将检验Gadd7受脂毒条件和功能调节的假设，以调节脂毒反应中的基因表达程序。我的目的是：1.确认Gadd7在脂毒反应中的作用；2.表征脂毒反应中Gadd7干扰抑制脂毒细胞死亡的步骤；3.通过评估Gadd7是否作为调节RNA来确定Gadd7在脂毒反应中的功能。脂肪的过度积累与心力衰竭和2型糖尿病等疾病的发病机制有关。这项拟议的研究将增加我们对过量脂肪如何扰乱器官功能的理解，从而有助于这些疾病的发病，并可能提供新的治疗和治疗途径。

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.