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）：小鼠已成为实验性急性肾损伤（AKI）和急性肾衰竭（ARF）研究中最常用的动物物种。这种偏好源于多种因素，包括相对成本、可用菌株的异质性、用于研究该物种的千变万化的分子探针的可用性，以及它们在诱导特定遗传改变（例如整个动物或组织特异性基因）方面的效用。淘汰赛。由于多种原因，大多数研究都是在小鼠出生后 4 个月内进行。然而，我们的实验室最近观察到，在这个早期成熟时期，对应于快速生长（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，虽然 1 个月大的小鼠几乎完全抵抗至少三种 ARF 模型，但遭受相同损伤方案的 4 个月大的小鼠会出现严重的肾小管坏死、管型形成和滤过失败。拟议工作的目标是更好地表征并初步了解这种从“抗损伤”表型到“损伤敏感”表型的转变是如何发生的。这项工作被认为很重要，原因如下：1）它可能对 AKI 未来研究的开展和解释具有潜在的深远影响； 2) 一般而言，可能会对细胞损伤的关键决定因素产生新的见解； 3) 了解为什么 1 个月大的小鼠对肾小管损伤具有很强的抵抗力可能会带来新的治疗见解。为此，提出了四个具体目标： 具体目标 1 将进一步描述这种成熟的决定因素 - 在整个动物水平上的 AKI 易感性效应（进一步定义年龄、性别和应变对 AKI 易感性和恢复率的影响）。损伤易感性的这种年龄依赖性转变是否是肾脏特异性的，或者是否也在肾外组织中表达，将被确定。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显着影响，则后续研究将旨在解决潜在的分子机制。具体目标 3 和 4 将进一步描述为什么两个关键的细胞保护途径 HMG CoA 还原酶（目标 3）和血红素加氧酶 1（目标 4）在早期成熟过程中不断变化，以及这些变化是否影响肾脏对 AKI 的易感性/ ARF。这些实验旨在生成（目标 1 和 2）并初步测试（目标 3 和 4）未来研究的新假设。因此，建议进行为期两年的研究（R-21）以获得初步见解，这将有助于更深入地关注未来的调查。公众健康相关性：随着动物（大概也包括人类）的成长和发育，它们的肾脏对损伤逐渐变得更加敏感。该应用的目标是确定发生这种情况的原因，因为这将产生对疾病机制的新见解。最终目标是开发药物策略，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的影响。