Using genomics to understand physiologic water conservation in desert rodents

目标1：确定沙漠适应啮齿动物生理水分保持的基因。目的2：将水分可利用性的细微变化与目的1中鉴定的基因差异表达联系起来。水平衡的维持是人体最重要的生理过程之一。事实上，人类和大多数其他哺乳动物对渗透压的变化非常敏感，轻微的紊乱会引起生理上的妥协。当失去的水分超过饮食摄入时，就会发生脱水。脱水是道德的重要来源，并可继发导致几种常见的临床疾病，包括急性肾损伤（AKI）和终末期肾衰竭（ESRD）。与大多数哺乳动物不同，生活在沙漠栖息地的动物要忍受长时间没有外来水源的折磨。因此，生活在这些环境中的动物已经进化出了一种机制，通过这种机制，即使在严重和长期脱水的情况下，也能维持生理稳态。更好地了解使适应沙漠的哺乳动物在没有水摄入的情况下生存的机制与人类健康直接相关，新的见解为制定旨在治疗和预防由脱水引起或与脱水相关的疾病的新策略提供了素材。由于脱水可导致肾脏疾病（影响数百万人（USRDS 2010）），因此迫切需要找到有效的治疗和预防策略。在这里，我建议研究功能性无尿症的基因组基础，这是适应沙漠的啮齿动物对缺乏外部水的适应-使用种内和种间水平的比较方法。具体来说，我将使用南加州Peromyscus属的三种啮齿动物来研究这一现象。其中，2种（P. eremicus和P. criinitus）适应沙漠，而第三种（P. maniculatus）是一个栖息地通才，但经常在极端干旱的非沙漠环境中发现。我将对每个物种的多个种群进行两次采样——一次是在没有外部水的旱季，另一次是在雨水充足的雨季。样品（mRNA分子）将进行全基因组分析（Illumina测序），基因表达将在不同季节进行比较。我将比较所有物种在干湿季节的基因表达。在旱季差异表达的基因很可能与节水有关。在干旱季节差异表达的一组基因中，那些适应沙漠的物种特有的基因可能对沙漠环境中的持久性至关重要（例如，可能是无尿症的基础）。

DESCRIPTION (provided by applicant): Aim 1: Identify genes underlying physiologic water conservation in desert-adapted rodents. Aim 2: Relate fine scale variation in water availability to differential expression of genes identified in Aim 1. The maintenance of water balance in humans is one of the most important physiologic processes. Indeed, humans and most other mammals are exquisitely sensitive to changes in osmolarity, with slight derangement eliciting physiologic compromise. When the loss of water exceeds dietary intake, dehydration occurs. Dehydration is an important source of morality, and can lead secondarily to several common clinical conditions including Acute Kidney Injury (AKI) and End- Stage Renal Failure (ESRD). Unlike most mammals, animals living in desert habitats are subjected to long periods during which no source of extrinsic water is available. As a result, animals living in these environments have evolved mechanisms through which physiologic homeostasis is maintained despite severe and prolonged dehydration. A better understanding of the mechanisms allowing desert-adapted mammals to survive without water intake is directly relevant to human health, with new insights providing fodder for the development of novel strategies aimed at the treatments and prevention of conditions caused by, or associated with, dehydration. Because dehydration can lead to kidney disease, (which affects millions of people (USRDS 2010)), finding effective strategies for its treatment and prevention is urgently needed. Here, I propose to study the genomic underpinnings of functional anuria, an adaptation to the absence of extrinsic water in desert-adapted rodents- using a comparative approach at the intra- and inter-specific levels. Specifically, I will study this phenomenon using three species of rodents within the genus Peromyscus in Southern California. Of these, 2 (P. eremicus and P. crinitus) are desert adapted while a 3rd (P. maniculatus) is a habitat generalist, but is often found in extremely arid non-desert environments. I will sample multiple populations of each species twice- once during the dry season when extrinsic water is unavailable, and once during the rainy reason, when water is maximally available. Samples (mRNA molecules) will be subjected to whole genome profiling (Illumina sequencing) and gene expression will be compared between seasons. I will compare gene expression in dry versus wet seasons in all species. Genes that are differentially expressed in the dry season are likely to be related to water conservation. Within the set of genes that are differentially expressed in the dry season, those that are specific to desert-adapted species are likely critical for persistence in desert environments (e.g., likely underlie anuria).