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: 8781566
• 负责人: Monica Chang-Panesso
• 金额: $ 6.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2015-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781566
• 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; 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(申请人提供)：根据美国人口普查局的统计数据，2050年，65岁及以上的美国人口预计为8850万，是2010年人口4020万的两倍多。这些老年人口的慢性肾脏疾病和急性肾脏损伤的患病率都较高。尽管人们对了解肾脏老化的机制和对损伤的易感性越来越感兴趣，但仍存在知识缺口。肾脏生物学的一个明显随年龄变化的方面是细胞周期的调节。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，而p16INK4A的水平在老年肾脏中明显上升。由于细胞增殖对肾脏的动态平衡和对损伤的反应至关重要，这一观察表明，衰老的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，它的表达在损伤和衰老过程中都会上升。Meis1是p16INK4a已知的转录激活子，因此在本研究中，我们假设Meis1通过上调p16INK4a来调节肾脏修复和衰老过程中的细胞衰老。为了研究这一假说，我们提出了三个具体目标。第一个目的是建立幼年和老年小鼠急性肾损伤后肾脏中Meis1的表达模式。在目标2中，我们将尝试确定Meis1在体外和体内损伤后肾小管增殖中的作用。在目标3中，将尝试研究Meis1缺失是否可以改善与年龄相关的纤维化、肾功能丧失和AKI的易感性。相关性：鉴于老龄化人口的增加和这一年龄段急性肾脏损伤和进展为慢性病的发生率的增加，这项研究的结果将有助于我们了解一种重要的临床情况，其在美国人口中的发病率正在上升。这反过来将导致合理的治疗策略，以防止老年人的肾脏损伤。