Characterizing the effects of Mouse Maturation on the Expression of Acute Renal F

表征小鼠成熟对急性肾 F 表达的影响

• 批准号: 7842690
• 负责人: Richard A. Zager
• 金额: $ 22万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842690
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Age; Age-Months; Aging; Animal Housing; Animals; Apoptosis; Azotemia; Biochemical Pathway; Body Weight; Cell membrane; Cells; Cessation of life; Cholesterol; Clinical; Cytoprotection; Cytoprotective Agent; Data; Disease; Failure; Female; Filtration; Future; Future Generations; Gene Targeting; Genes; Genomics; Glycolysis; Goals; Heterogeneity; Human; Hydrolysis; Hydroxymethylglutaryl-CoA reductase; Inflammation; Injury; Investigation; Kidney; Laboratories; Laboratory mice; Lead; Life; Liver; Maleates; Modeling; Molecular; Molecular Probes; Morbidity - disease rate; Mus; Mutation; Nature; Organ; Oxidative Stress; Pathway interactions; Patients; Phenotype; Phospholipids; Predisposition; Prevention approach; Process; Protocols documentation; RNA Polymerase II; Recovery; Relative (related person); Renal Tissue; Resistance; Rhabdomyolysis; Rodent; Severities; Staging; Testing; Time; Tissues; Tubular formation; Work; age related; base; cell injury; cost; design; expectation; heme oxygenase-1; hemodynamics; high risk; insight; male; mortality; novel therapeutics; oxidant stress; preference; public health relevance; rapid growth; research study; sex; stem; transcription factor; tubular necrosis; weight maintenance

DESCRIPTION (provided by applicant): Mice have become the most commonly used animal species for studies of experimental acute kidney injury (AKI) and acute renal failure (ARF). This preference stems from a variety of factors, including relative cost, the heterogeneity of available strains, the availability of protean molecular probes for studying this species, and their utility for induction of specific genetic alterations, such as whole animal- or tissue specific- gene knock-outs. For a variety of reasons, most studies are performed when the mice are within the first 4 months of life. However, our laboratory has recently observed that during this early maturation period, which corresponds with rapid growth (e.g., a 3x increase in body weight), there is a profound change in renal susceptibility to diverse forms of attack. Thus, whereas 1 month old mice are almost completely resistant to at least three ARF models, 4 month old mice subjected to the same injury protocols sustain severe tubular necrosis, cast formation, and filtration failure. The goal of the proposed work is to better characterize, and to gain initial insights into, how this change from an "injury resistant" to an "injury sensitive" phenotype occurs. This work is deemed to be important for the following reasons: 1) it may have potentially profound implications for the conduct, and interpretation of, future studies of AKI; 2) new insights into critical determinants of cellular injury, in general, could result; and 3) understanding why 1 month old mice have profound resistance to tubular injury could potentially lead to new therapeutic insights. Towards these ends, four Specific Aims are proposed: Specific Aim 1 will further characterize determinants of this maturation - AKI susceptibility effect at the whole animal level (further definition of age, sex, and strain effects on AKI susceptibility and recovery rates). Whether this age dependent switch in injury susceptibility is renal specific, or whether it is also expressed in extra-renal tissues, will be determined. Specific Aim 2 will assess potential biochemical pathways through which this changing cell phenotype occurs (primary alterations in cellular energetics, oxidant stress, phospholipid hydrolysis, inflammation, apoptosis). If the maturation process has a dominant impact on a specific injury- inducing pathway, subsequent studies will be designed to address underlying molecular mechanisms. Specific Aims 3 and 4 will further characterize why two critical cytoprotective pathways, HMG CoA reductase (Aim 3), and heme oxygenase-1 (Aim 4), are in flux during the early maturation process, and whether these changes impact renal susceptibility to AKI / ARF. These experiments have been designed to generate (Aims 1 & 2), and preliminarily test (Aim 3 &4), new hypotheses for future study. Hence, a two year study (R-21) is proposed to gain initial insights that will help focus more in depth future investigation. PUBLIC HEALTH RELEVANCE: As animals, and presumably humans, grow and develop, their kidneys become progressively more sensitive to injury. The goal of this application is to determine why this occurs, because this will yield new insights into mechanisms of disease. The ultimate goal is to develop pharmacologic strategies that can protect high risk patients from the onset of severe, acute kidney injury and its adverse sequelae that frequently result in death.

描述（由申请方提供）：小鼠已成为实验性急性肾损伤（阿基）和急性肾衰竭（ARF）研究中最常用的动物种属。这种偏好源于多种因素，包括相对成本、可用菌株的异质性、用于研究该物种的多变分子探针的可用性，以及它们用于诱导特定遗传改变（例如全动物或组织特异性基因敲除）的效用。由于各种原因，大多数研究都是在小鼠出生后的前4个月内进行的。然而，我们的实验室最近观察到，在与快速生长相对应的早期成熟期（例如，体重增加3倍），肾脏对各种形式的攻击的敏感性发生了深刻的变化。因此，尽管1月龄小鼠几乎完全抵抗至少三种ARF模型，但经受相同损伤方案的4月龄小鼠维持严重的肾小管坏死、管型形成和滤过失败。所提出的工作的目标是更好地表征，并获得初步的见解，如何从“损伤抗性”到“损伤敏感”表型发生这种变化。由于以下原因，这项工作被认为是重要的：1）它可能对阿基未来研究的进行和解释具有潜在的深远影响; 2）通常可能导致对细胞损伤关键决定因素的新见解;以及3）理解为什么1个月大的小鼠对肾小管损伤具有深刻的抵抗力可能会导致新的治疗见解。为此，提出了四个具体目标：具体目标1将进一步表征这种成熟的决定因素-整个动物水平的阿基易感性效应（进一步定义年龄、性别和品系对阿基易感性和恢复率的影响）。将确定这种损伤易感性的年龄依赖性转换是否是肾特异性的，或者它是否也在肾外组织中表达。具体目标2将评估发生这种变化的细胞表型的潜在生化途径（细胞能量学、氧化应激、磷脂水解、炎症、细胞凋亡的主要改变）。如果成熟过程对特定的损伤诱导途径具有主导影响，则后续研究将被设计为解决潜在的分子机制。具体目标3和4将进一步表征两个关键细胞保护途径HMG CoA还原酶（Aim 3）和血红素加氧酶-1（Aim 4）在早期成熟过程中发生变化的原因，以及这些变化是否影响肾脏对阿基/ ARF的易感性。这些实验旨在产生（目标1和2），并初步测试（目标3和4），为未来的研究新的假设。因此，提出了一项为期两年的研究（R-21），以获得初步的见解，这将有助于集中在更深入的未来调查。公共卫生相关性：随着动物（大概也包括人类）的生长和发育，它们的肾脏对损伤越来越敏感。该应用程序的目标是确定为什么会发生这种情况，因为这将产生对疾病机制的新见解。最终目标是开发药理学策略，可以保护高危患者免于发生严重的急性肾损伤及其不良后遗症，这些后遗症经常导致死亡。