Role of carboxyl-terminal modulator protein in autophagy and senescence of human induced pluripotent stem cells

阿尔茨海默病(AD)是老年人中最常见的痴呆症。衰老是最重要的 阿尔茨海默病最重要的危险因素。众所周知，大脑老化伴随着自噬的减少，一种 清除受损细胞器和错误折叠蛋白质的生物过程。我们已经证明了 随着年龄的增长，大鼠脑组织中的羧基末端调节蛋白(CTMP)含量增加。我们的 由父母赠款支持的正在进行的研究表明，CTMP的增加有助于 减少了大鼠脑内的自噬。我们的初步数据显示， 老年人脑内CTMP基因表达水平升高。有可能我们在老鼠身上的发现 可能适用于人类。由于自噬减少可能导致细胞衰老， CTMP对细胞衰老有调节作用。然而，CTMP在细胞衰老中的作用并不是 在啮齿动物和人类中已知。因此，我们假设CTMP减少了自噬和 阿尔茨海默病或非阿尔茨海默病对人诱导多能干细胞的诱导衰老 病理学。我们将在这个补充请求项目中验证这一假设。使用IPSC 因为不可能在活体条件下在人类身上测试我们的假设 IPSC在多种疾病的细胞治疗方面具有巨大的潜力。IPSC生成自 健康人或AD突变患者将感染慢病毒以 过度表达CTMP或抑制CTMP表达。这些牢房将接受 自噬和细胞衰老。这些研究可能确定一个需要改进的分子靶点。 促进IPSC的健康，促进我们对细胞分子过程的认识 存在或不存在AD病理的衰老，一种衰老依赖 神经病理学。

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Aging is the most significant risk factor for AD. It is known that brain aging is with decreased autophagy, a biological process to clean damaged organelles and misfolded proteins. We have shown that carboxyl-terminal modulator protein (CTMP) is increased in the brain with aging in rats. Our ongoing study supported by the parent grant has shown that CTMP increase contributes to the decreased autophagy in the brain of rats. Our preliminary data showed that there was an increase in CTMP mRNA levels in the brain of old people. It is possible that our findings in rats may be applicable in humans. Since decreased autophagy may contribute to cell senescence, CTMP may regulate cell senescence. However, the role of CTMP in cell senescence is not known in rodents and humans. Thus, we hypothesize that CTMP reduces autophagy and induces senescence in the human induced pluripotent stem cells (iPSC) with or without AD pathology. We will test this hypothesize in this supplement request project. iPSC is used because it is not possible to test our hypothesis in humans under in vivo conditions and iPSC holds a great potential in cell therapy for various diseases. iPSC generated from healthy individual or from a patient with an AD mutation will be infected with lentivirus to overexpress CTMP or silence CTMP expression. These cells will be subject to the evaluation of autophagy and cell senescence. These studies may identify a molecular target for improving the health of iPSC and advance our knowledge on the molecular process of cell senescence in the presence or absence of AD pathology, an aging-dependent neuropathology.