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

羧基末端调节蛋白在人诱导多能干细胞自噬和衰老中的作用

基本信息

批准号：
10756824
负责人：
Ian Christopher Wenker
金额：
$ 40.16万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10756824
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Attenuated Autophagocytosis Biological Biological Process Brain Cell Aging Cell Cycle Cell Proliferation Cell Therapy Cell physiology Cells Code Data Dementia Disease Down-Regulation Elderly Embryo Evaluation Funding Genes Genetic Transcription Health Homeostasis Human Impairment Individual Ischemia Knowledge Learning Lentivirus Memory Messenger RNA Methods Modeling Molecular Molecular Target Mutation Neurodegenerative Disorders Organelles PIK3CG gene Pathway interactions Play Process Protein Overexpression Proteins Proto-Oncogene Proteins c-akt Rattus Regulation Rodent Role Societies Structure Testing Therapeutic aging brain beta-Galactosidase brain cell cell replacement therapy cell type experimental study family burden improved in vivo induced pluripotent stem cell inhibition of autophagy kidney cell misfolded protein molecular marker neuropathology overexpression parent grant parent project protein expression protein phosphatase inhibitor-2 senescence small hairpin RNA transcription factor

项目摘要

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.

阿尔茨海默病（AD）是老年人最常见的痴呆症。众所周知，AD 最重要的危险因素是自噬的减少，这是大脑衰老的一个原因。我们已经证明了清洁受损细胞器和错误折叠蛋白质的生物过程。随着大鼠衰老，其大脑中的羧基末端调节蛋白（CTMP）会增加。由家长资助支持的正在进行的研究表明，CTMP 的增加有助于我们的初步数据表明，大鼠大脑中的自噬减少。老年人大脑中 CTMP mRNA 水平的增加可能与我们在大鼠中的发现一致。可能适用于人类，因为自噬减少可能导致细胞衰老， CTMP可能调节细胞衰老，但CTMP在细胞衰老中的作用却并非如此。因此，我们认为 CTMP 会减少自噬并减少自噬。诱导患有或不患有 AD 的人类诱导多能干细胞 (iPSC) 衰老我们将测试此补充请求项目中所追求的。因为不可能在体内条件下在人体中检验我们的假设 iPSC 在治疗各种疾病方面具有巨大潜力。健康个体或患有 AD 突变的患者将被慢病毒感染过表达 CTMP 或沉默 CTMP 表达这些细胞将受到评估。这些研究可能会确定改善自噬和细胞衰老的分子靶标。 iPSC 的健康并增进我们对细胞分子过程的了解在存在或不存在 AD 病理学的情况下衰老，这是一种衰老依赖性的疾病神经病理学。