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: 7631730
• 负责人: Richard A. Zager
• 金额: $ 26.4万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631730
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; 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(由申请人提供)：小鼠已成为研究实验性急性肾损伤(AKI)和急性肾功能衰竭(ARF)最常用的动物物种。这种偏好源于多种因素，包括相对成本、现有菌株的异质性、用于研究该物种的蛋白质分子探针的可用性，以及它们对诱导特定遗传改变的有效性，例如整个动物或组织特异性基因敲除。由于各种原因，大多数研究都是在小鼠出生后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)，肾脏对各种形式攻击的易感性发生了深刻的变化。因此，1个月大的小鼠对至少三种ARF模型几乎完全耐受，而4个月大的小鼠在相同的损伤方案下出现严重的肾小管坏死、管型形成和滤过失败。这项拟议工作的目标是更好地刻画并初步了解这种从“伤害抵抗”到“伤害敏感”表型的变化是如何发生的。这项工作被认为很重要，原因如下：1)它可能对AKI的进行和解释产生潜在的深远影响；2)对细胞损伤的关键决定因素可能会产生新的见解；以及3)理解为什么1个月大的小鼠对肾小管损伤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将在整个动物水平上进一步描述这种成熟-AKI易感性效应的决定因素(进一步定义年龄、性别和应变对AKI易感性和恢复率的影响)。这种损伤易感性的年龄依赖性开关是肾脏特有的，还是在肾外组织中也有表达，将被确定。具体目标2将评估发生这种细胞表型变化的潜在生化途径(细胞能量学的主要变化、氧化应激、磷脂水解、炎症、细胞凋亡)。如果成熟过程对特定的损伤诱导途径具有主导影响，后续研究将被设计用于解决潜在的分子机制。特定的AIMS 3和4将进一步描述为什么两个关键的细胞保护通路，HMG CoA还原酶(AIM 3)和血红素加氧酶-1(AIM 4)在早期成熟过程中处于流动状态，以及这些变化是否影响肾脏对AKI/ARF的易感性。这些实验旨在为未来的研究产生新的假设(目标1和2)，并初步检验(目标3和4)。因此，建议进行一项为期两年的研究(R-21)，以获得初步的见解，这将有助于将重点放在未来更深入的调查上。与公共卫生相关：随着动物，大概还有人类的成长和发育，它们的肾脏对伤害越来越敏感。这项应用的目标是确定为什么会发生这种情况，因为这将对疾病的机制产生新的见解。最终目标是开发能够保护高危患者免受严重、急性肾损伤及其经常导致死亡的不良后遗症影响的药物策略。