Meis1 and Cell Cycle in Kidney Injury and Aging

Meis1 和细胞周期在肾损伤和衰老中的作用

基本信息

批准号：
8906491
负责人：
Monica Chang-Panesso
金额：
$ 6.48万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-03 至 2016-07-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906491
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Age Age Factors Aging American Amino Acids Apoptosis Biological Assay Biological Markers Biology CDKN2A gene Cardiac Myocytes Cell Aging Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Proliferation Cellular Stress Censuses Characteristics Chronic Disease Chronic Kidney Failure Clinical Cyclin D1 Cyclin E Cyclin-Dependent Kinases Cyclins Data Elderly Epithelial Cells Family Fibrosis Figs - dietary G1 Arrest Genes High Prevalence Homeostasis Human Immunofluorescence Immunologic In Situ In Vitro Incidence Injury Kidney Knock-out Knowledge Lead Measures Mediating Meis1 protein Messenger RNA Mitochondria Mus Natural regeneration Nephrons Nuclear Older Population Oxidative Stress Patients Pattern Physiological Population Predisposition Proliferating Proteins Recording of previous events Regulator Genes Renal function Reporting Risk Rodent Role Stress Syndrome Testing Therapeutic Transcription Coactivator Tubular formation Tumor Suppressor Proteins United Nations United States Up-Regulation age group age related aged aging population base cohort differential expression homeodomain in vivo in vivo Model interest interstitial kidney repair normal aging postnatal premature prevent public health relevance repaired response to injury senescence statistics transcription factor

项目摘要

DESCRIPTION (provided by applicant): Based on statistics from the US Census Bureau, in 2050, the number of Americans aged 65 and older is projected to be 88.5 million, more than double the population of 40.2 million in 2010. This older population carries a higher prevalence of both chronic kidney disease and acute kidney injury. Despite increasing interest in understanding the mechanisms of kidney aging and susceptibility to injury, there is a knowledge gap. One aspect of kidney biology that clearly changes with aging is regulation of the cell cycle. For example, p16INK4a is a gene that inhibits the cell cycle by controlling the activity of cyclin-dependent kinases, and levels of p16INK4A clearly rise in aged kidney. Since cell proliferation is crucial for kidney homeostasis and response to injury, this observation suggests that aged kidneys may be more susceptible to injury because they have decreased capacity to proliferate. We have recently identified a new cell cycle regulatory gene, Meis1, whose expression also rises both in response to injury and during aging. Meis1 is a known transcriptional activator of p16INK4a, and therefore in this proposal we hypothesize that Meis1 regulates cell senescence during kidney repair and during aging via up regulation of p16INK4a. To investigate this hypothesis, three specific aims are proposed. The first aim is to establish the expression pattern of Meis1 in the kidney at baseline and after acute kidney injury in young and aged mice. In aim 2, we will try to define the role of Meis1 in renal tubular proliferation in vitro and in vivo afte injury. In aim 3 will try to investigate whether Meis1 deletion ameliorates age-related fibrosis, loss of kidney function and susceptibility to AKI. Relevance: Given the rise in the aging population and the increase incidence of acute kidney injury and progression to chronic disease in this age group, the results of this study will help us to understand an important clinical condition whose incidence is rising in the US population. This in turn will lead to rational therapeutic strategies to prevent kidney injury among the elderly.

描述（由申请人提供）：根据美国人口普查局的统计数据，2050年，65岁及65岁以上的美国人的数量预计为8850万，是2010年的4020万人的两倍以上。该老年人口的患病率较高，其慢性肾脏病和急性肾脏受伤的患病率更高。尽管对了解肾脏衰老的机制和受伤的易感性的兴趣越来越大，但知识差距仍然存在。肾脏生物学的一个方面显然随老化而变化的是细胞周期的调节。例如，P16INK4A是一种通过控制细胞周期蛋白依赖性激酶的活性而抑制细胞周期的基因，而P16INK4A的水平显然在老年肾脏中升高。由于细胞的增殖对于肾脏稳态至关重要，并且对损伤的反应至关重要，因此该观察结果表明，老年肾脏可能更容易受伤，因为它们的增殖能力降低。我们最近确定了一个新的细胞周期调节基因MEIS1，其表达也会响应损伤和衰老期间。 MEIS1是p16Ink4a的已知转录激活因子，因此在此提案中，我们假设Meis1在肾脏修复期间和衰老期间通过调节P16INK4A调节细胞衰老。为了研究这一假设，提出了三个具体目标。第一个目的是在基线时在肾脏和年龄小鼠急性肾损伤后建立MEIS1的表达模式。在AIM 2中，我们将尝试定义MEIS1在体外和体内损伤中的肾小管增殖中的作用。在AIM 3中，将尝试调查MEIS1缺失是否可以缓解与年龄相关的纤维化，肾功能的丧失和对AKI的易感性。相关性：鉴于人口老龄化的增长以及该年龄段的急性肾脏损伤和慢性疾病进展的发生率的增加，这项研究的结果将帮助我们了解一个重要的临床状况，该临床状况在美国人群中的发生率正在上升。反过来，这将导致预防老年人肾脏损伤的理性治疗策略。