ARID3a, a repressor in aged kidney progenitors?

摘要 ARID3a是一种dna结合蛋白，是与表观遗传学相关的蛋白质大家族的成员。 功能。ARID3a在造血祖细胞中表达，但其表达和功能发生变化 随着年龄的增长。我们最近的研究表明，ARID3a可以在多种类型的细胞中被诱导表达 与炎症过程相关的健康成人，特别是与I型表达相关的 干扰素。在成体细胞类型中诱导ARID3a导致差异基因表达模式 特定于单元类型的。我们将ARID3a的表达与小鼠的肾脏发育联系起来，在小鼠中，缺乏 在大量培养的小鼠肾脏中，ARID3a导致了发育可塑性细胞的产生。令人惊讶的是， 这些细胞自发发育成表达成熟肾脏标志物的复杂结构 电镀在半固体培养物中。这一发现使我们确定ARID3a是否在成人中表达 肾脏。我们的初步数据表明，ARID3a在人类肾脏中的表达似乎增加了 随着年龄的增长，它在具有祖细胞表面标记的细胞的三个亚群中共表达。相同 年轻个体的亚群几乎不表达ARID3a。我们假设ARID3a表达增加 与细胞相比，老年人中表达ARID3a的肾脏前体细胞的功能受损 来自表达较低水平ARID3a的年轻个体。在目标1中，我们将通过以下方式验证这一假设 抑制老年人这三个细胞亚群中ARID3a的表达 这些细胞在体外增殖和分化为来自相同ARID3a个体的细胞。我们会 还要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变化。在目标2中，我们将确定 在老年祖细胞中受ARID3a表达影响的基因和途径确定 路径(S)与老年肾脏反应性降低有关。总之，这些实验将提供 关于ARID3a对老年肾脏的潜在影响的新信息，并最终可能导致新的 肾脏修复治疗学。此外，这些研究的结果可能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.