Ontogenic changes in injury-induced gene expression

损伤诱导的基因表达的个体发生变化

• 批准号: 7110279
• 负责人: GORDON Alfred BARR
• 金额: $ 17.93万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110279
• 关键词: behavior test; carrageenan; developmental genetics; developmental neurobiology; dorsal horn; gene expression; hyperalgesia; laboratory rat; microarray technology; nerve injury; neural information processing; neural transmission; neurogenetics; oligonucleotides; pain

DESCRIPTION (provided by applicant): One of the difficulties in developing treatments for the seriously ill infant patient has been the limited understanding of how pain processing differs between the infant and the adult. In particular, there are developmental differences in how pain is processed, and in the long-term consequences of tissue insult. Growing evidence both from the clinic and the laboratory demonstrate that there are long lasting changes in sensitivity to subsequent noxious stimuli following injury in the infant. Further, there appears to be a "critical" period, at least in the rat, such than injury in the first two weeks of life, but not later, results in those long lasting changes in pain sensitivity. This clearly has very important clinical implications; yet nothing is known of the mechanisms engaged by the experience of pain in early development. The recent development of microarray methods to assess simultaneously changes in the expression in thousands of genes provides a unique opportunity to define the neural and genetic changes that might be responsible for the differences in pain processing in infants, immediately and in the 24 hours after injury, and into adulthood. Here we propose to use well-characterized oligonucleotide microarrays (Affymetrix) and state of the art analytic methods to define those alterations in gene expression induced by injury. We assay the dorsal horn of the lumbar enlargement of the spinal cord as a model system, largely because of described short and long terms changes in spinal cord function and neurobiology induced by injury. We test rat pups at 3 and 21 days of age and assess gene expression changes at four times after insult over 24 hours. This describes the more immediate changes in gene expression as a function of injury. The second series of studies examine changes in gene expression in the adult spinal cord in pups injured at different ages in early in development. In the putative critical period, during the first two weeks of life, pups are injected with carrageenan. Older pups are tested because they are outside the critical period. Adults treated as pups are tested again, with or without insult, and gene expression is assayed by microarray. The results of these experiments will define in detail, changes in gene expression that are induced by injury early in development when nociceptive processes are distinctly different than the adult, and again later in development, after the end of the critical period. Further, we describe long-term changes in expression that might explain the "permanent" changes in pain perception induced by early injury. These data will provide the basis of rational treatments that might reduce any deleterious effects of pain experience by premature and seriously ill infants.

描述（由申请人提供）：为重病婴儿患者开发治疗方法的困难之一是对婴儿和成人之间疼痛处理方式的差异了解有限。特别是，疼痛的处理方式以及组织损伤的长期后果存在发育差异。来自诊所和实验室的越来越多的证据表明，婴儿受伤后对随后的有害刺激的敏感性会发生长期持续的变化。此外，似乎存在一个“关键”时期，至少在大鼠中，例如在生命的前两周内受伤，但之后不会导致疼痛敏感性的持久变化。这显然具有非常重要的临床意义；然而，对于早期发育过程中的痛苦经历所涉及的机制却一无所知。最近开发的微阵列方法可同时评估数千个基因表达的变化，这提供了一个独特的机会来定义神经和遗传变化，这些变化可能导致婴儿、受伤后立即和24小时内以及成年后疼痛处理的差异。在这里，我们建议使用充分表征的寡核苷酸微阵列（Affymetrix）和最先进的分析方法来定义损伤诱导的基因表达的改变。我们将脊髓腰椎增大的背角作为模型系统进行分析，很大程度上是因为描述了损伤引起的脊髓功能和神经生物学的短期和长期变化。我们对 3 天和 21 天龄的幼鼠进行了测试，并在 24 小时内的侮辱后四次评估了基因表达变化。这描述了基因表达因损伤而发生的更直接的变化。第二系列研究检查了在发育早期不同年龄受伤的幼崽中成年脊髓基因表达的变化。在假定的关键期，即生命的前两周，幼犬被注射角叉菜胶。较大的幼崽需要接受测试，因为它们已经过了关键期。再次对作为幼崽处理的成体进行测试，无论有没有损伤，并通过微阵列测定基因表达。这些实验的结果将详细定义基因表达的变化，这些变化是在发育早期（当伤害感受过程与成人明显不同时）由损伤引起的，以及在发育后期（关键期结束后）引起的。此外，我们描述了表达的长期变化，这可能解释了早期损伤引起的疼痛感知的“永久性”变化。这些数据将为合理治疗提供基础，可能减少早产儿和重病婴儿疼痛经历的任何有害影响。