Using genomics to understand physiologic water conservation in desert rodents

描述（由申请人提供）：目的1：确定适应沙漠的啮齿动物中生理性水资源保护的基因。目的2：将水可用性的精细尺度变化与目的1中鉴定的基因的差异表达联系起来。 维持人体水分平衡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损害。当水分流失超过饮食摄入量时，就会发生脱水。脱水是死亡的重要来源，并且可继发地导致几种常见的临床病症，包括急性肾损伤（阿基）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长期没有外来水源。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，尽管严重和长期脱水，但仍能维持生理稳态。更好地了解机制，使适应沙漠的哺乳动物生存没有水的摄入量直接关系到人类健康，新的见解提供饲料的发展，旨在治疗和预防的条件所造成的，或相关的，脱水的新战略。由于脱水可能导致肾脏疾病（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的基因组基础，适应沙漠适应啮齿动物的外部水的情况下-使用比较的方法在内部和种间水平。 具体来说，我将研究这一现象，使用三种啮齿动物属内的Peromyscus在南加州。其中，2种（P. eremicus和P. crinitus）是沙漠适应者，而第3种（P. maniculatus）是一种生境通才，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--一次是在干旱季节，外部水不可用，另一次是在雨季，水最多的时候。将对样本（mRNA分子）进行全基因组分析（Illumina测序），并比较不同季节的基因表达。我将比较所有物种在旱季和雨季的基因表达。在干旱季节差异表达的基因可能与节水有关。在旱季差异表达的基因组中，那些对沙漠适应物种特异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).