Using genomics to understand physiologic water conservation in desert rodents

利用基因组学了解沙漠啮齿动物的生理水分保护

• 批准号: 8202688
• 负责人: Matthew David MacManes
• 金额: $ 4.63万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202688
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animals; Anuria; Biological Assay; California; Clinical; Coupled; Dehydration; Development; Dietary intake; End stage renal failure; Environment; Equilibrium; Gene Expression; General Practitioners; Genes; Genome; Genomics; Habitats; Health; Homeostasis; Human; Kidney Diseases; Lead; Life; Maintenance; Mammals; Messenger RNA; Methods; Morality; Osmolar Concentration; Peromyscus; Phylogenetic Analysis; Physiological; Physiological Processes; Population; Prevention; Research; Rodent; Sampling; Seasons; Social Welfare; Source; Specimen; Taxon; Testing; Tissue-Specific Gene Expression; Tissues; Training; Variant; Water; Water consumption; comparative; insight; novel strategies; water conservation

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). PUBLIC HEALTH RELEVANCE: The research described in this proposal will reveal the genomic underpinnings of physiologic water conservation (e.g. anuria), an adaptation to the absence of extrinsic water, in desert- adapted rodents. 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 novel strategies aimed at the treatments and prevention of conditions caused by, or associated with, dehydration. Because these conditions affect millions of people, finding effective strategies for its treatment and prevention is urgently needed.

描述(由申请者提供)：目标1：确定沙漠适应啮齿动物生理性水源保护的基因。目的2：水可利用性的细微尺度变化与目的1中确定的基因的差异表达有关。维持人体水平衡是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，轻微的排列紊乱会导致生理上的妥协。当失水量超过饮食摄入量时，就会发生脱水。脱水是死亡的一个重要来源，并可继发导致几种常见的临床情况，包括急性肾损伤(AKI)和终末期肾功能衰竭(ESRD)。与大多数哺乳动物不同，生活在沙漠栖息地的动物要经历很长一段时间，在此期间没有外部水源。因此，生活在这些环境中的动物进化了一些机制，通过这些机制，即使严重和长期脱水，也能保持生理稳态。更好地了解允许适应沙漠的哺乳动物在不摄入水的情况下存活的机制与人类健康直接相关，新的见解为开发旨在治疗和预防脱水引起或与之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，我建议使用种内和种间水平的比较方法来研究功能性无尿的基因组基础，功能性无尿是一种对沙漠适应啮齿动物缺乏外源性水的适应。具体地说，我将使用南加州Permyscus属的三种啮齿动物来研究这种现象。其中，2个(P.eremicus和P.crintes)适应沙漠，而第3个(P.manulatus)是栖息地通才，但通常发现于极端干旱的非沙漠环境。我将对每个物种的多个种群进行两次采样--一次是在没有外来水分的旱季，另一次是在下雨的时候，当水最多的时候。样本(mRNA分子)将受到全基因组图谱(Illumina测序)的影响，基因表达将在不同季节进行比较。我将比较所有物种在旱季和雨季的基因表达。旱季差异表达的基因可能与节水有关。在旱季差异表达的一组基因中，那些特定于沙漠适应物种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)。 与公共健康相关：这项建议中描述的研究将揭示生理性保水(例如，无尿)的基因组基础，这是对沙漠适应啮齿动物缺乏外部水的一种适应。更好地了解允许适应沙漠的哺乳动物在不摄入水的情况下存活的机制与人类健康直接相关，新的见解为旨在治疗和预防脱水引起或相关疾病的新战略提供了素材。由于这些疾病影响着数百万人，因此迫切需要找到有效的治疗和预防策略。