ARID3a, a repressor in aged kidney progenitors?

摘要 ARID3a是一种DNA结合蛋白，是与表观遗传相关的蛋白质大家族的成员， 功能协调发展的ARID3a在造血祖细胞中表达，其中其表达和功能被改变 随年龄我们最近的研究表明，ARID3a表达可以在多种细胞类型中诱导， 与炎症过程相关的健康成人，特别是与I型 干扰素在成体细胞类型中诱导ARID3a导致差异基因表达模式， 细胞类型特异性。我们将ARID3a表达与小鼠肾脏发育联系起来，在缺乏ARID3a的小鼠中， 大量培养的小鼠肾脏中的ARID3a导致发育可塑性细胞的产生。令人惊讶的是， 这些细胞自发地发育成表达成熟肾脏标记物的复杂结构， 接种于半固体培养物中。这一发现使我们能够确定ARID3a是否在人类成人中表达。 肾脏我们的初步数据表明，ARID3a在人肾脏中的表达似乎增加， 随着年龄的增长，它与祖细胞表面标志物共表达在三个细胞亚群中。相同的 来自年轻个体的亚群表达很少的ARID3a。我们假设ARID3a表达的增加 与细胞相比，在老年人中， 年轻人中ARID3a的表达水平较低。在目标1中，我们将通过以下方式检验这一假设： 抑制来自老年个体的这三种细胞亚群中的ARID3a表达，并比较 这些细胞在体外增殖并分化为来自具有ARID3a的相同个体的细胞。我们将 还将这些细胞与年轻人的祖细胞进行比较。此外，我们假设ARID3a改变了 老年人的基因表达模式导致功能改变。在目标2中，我们将确定 在老年人祖细胞中受ARID3a表达影响的基因和途径，以确定 与老化肾脏反应降低相关的通路。这些实验将提供 关于ARID3a在老年肾脏中的潜在影响的新信息，并可能最终导致新的 肾脏修复的治疗方法。此外，这些研究的结果可能会确定与衰老相关的标志物， 以及其他组织的炎症反应。

Abstract ARID3a, a DNA-binding protein, is a member of a large family of proteins associated with epigenetic functions. ARID3a is expressed in hematopoietic progenitors where its expression and functions are altered with age. Our recent studies indicate that ARID3a expression can be induced in multiple cell types from healthy adults in association with inflammatory processes, and particularly with expression of Type I interferons. Induction of ARID3a in adult cell types leads to differential gene expression patterns that are cell type-specific. We linked ARID3a expression to kidney development in the mouse, where absence of ARID3a in bulk-cultured mouse kidneys resulted in generation of developmentally plastic cells. Surprisingly, these cells spontaneously developed into complex structures that express mature kidney markers when plated in semi-solid cultures. This finding led us to determine if ARID3a is expressed in human adult kidneys. Our preliminary data indicate that ARID3a expression in the human kidney appears to increase with age and that it is co-expressed in three subsets of cells with progenitor surface markers. The same subsets from younger individuals express little ARID3a. We hypothesize that increased ARID3a expression in aged individuals impairs the functions of those ARID3a-expressing kidney progenitors compared to cells from younger individuals that express lower levels of ARID3a. In Aim 1, we will test this hypothesis by inhibiting ARID3a expression in these three cell subsets from aged individuals and comparing the ability of those cells to proliferate and differentiate in vitro to cells from the same individuals with ARID3a. We will also compare these cells to progenitors from younger adults. Further, we hypothesize that ARID3a alters gene expression patterns in aged individuals resulting in changes in function. In Aim 2, we will identify genes and pathways affected by ARID3a expression in older adult progenitor cells to determine the pathway(s) associated with decreased responses in aged kidneys. Together, these experiments will provide new information about the potential effects of ARID3a in aged kidneys and could ultimately result in new therapeutics for kidney repair. In addition, results from these studies may identify markers relevant for aging and inflammatory responses in other tissues.