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

• 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
• 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

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，到2050年，65岁及以上的美国人预计将达到8850万，是2010年4020万人口的两倍多。这一老年人群的慢性肾脏疾病和急性肾损伤患病率较高。尽管越来越多的人对了解肾脏衰老和损伤易感性的机制感兴趣，但仍存在知识缺口。肾脏生物学的一个方面，随着年龄的增长而明显变化，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来抑制细胞周期的基因，并且p16INK4A的水平在老年肾脏中明显升高。由于细胞增殖对于肾脏稳态和对损伤的反应至关重要，因此这一观察结果表明，老年肾脏可能更容易受到损伤，因为它们的增殖能力降低。我们最近发现了一个新的细胞周期调控基因Meis1，其表达在损伤和衰老过程中也会增加。Meis1是已知的p16INK4a的转录激活因子，因此在本提案中，我们假设Meis1通过上调p16INK4a来调节肾脏修复期间和衰老期间的细胞衰老。为了研究这一假设，提出了三个具体目标。第一个目的是建立Meis1在年轻和老年小鼠基线和急性肾损伤后肾脏中的表达模式。目的2：探讨Meis 1在体外和体内肾小管损伤后的增殖中的作用。目标3将尝试研究Meis1缺失是否改善年龄相关性纤维化、肾功能丧失和对阿基的易感性。相关性：鉴于人口老龄化的增加以及该年龄组急性肾损伤和慢性疾病进展的发生率增加，本研究的结果将有助于我们了解美国人群中发病率不断上升的重要临床疾病。这反过来又会导致合理的治疗策略，以防止老年人的肾损伤。