Meis1 and Cell Cycle in Kidney Injury and Aging

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，美国65岁及以上的人口预计将达到8850万，比2010年的4020万增加一倍多。老年人群中慢性肾脏疾病和急性肾损伤的患病率较高。尽管人们对了解肾脏衰老和损伤易感性的机制越来越感兴趣，但仍存在知识缺口。肾脏生物学的一个方面是细胞周期的调节，随着年龄的增长而明显改变。例如，p16INK4a是一种通过控制周期蛋白依赖性激酶的活性来抑制细胞周期的基因，在老年肾脏中p16INK4a的水平明显升高。由于细胞增殖对肾脏稳态和损伤反应至关重要，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下降。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转录激活因子，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。为了研究这一假设，提出了三个具体目标。第一个目的是建立Meis1在幼年和老年小鼠急性肾损伤时和急性肾损伤后肾脏中的表达模式。在目的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。目的3将试图研究Meis1缺失是否能改善年龄相关性纤维化、肾功能丧失和AKI易感性。相关性：鉴于老龄化人口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，本研究的结果将帮助我们了解美国人群中发病率正在上升的重要临床疾病。这反过来将导致合理的治疗策略，以防止老年人肾损伤。

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.