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的不同程度有限。特别是，在组织的处理方式以及组织侮辱的长期后果方面存在发育差异。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有很长的变化。此外，至少在大鼠中，似乎有一个“关键”时期，例如在生命的前两周而不是受伤，但不以后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，痛苦在早期发展中所涉及的机制尚未知道。微阵列方法的最新开发用于评估数千个基因中表达的同时变化，这为定义神经和遗传变化提供了独特的机会，这可能导致婴儿的疼痛处理差异，并在受伤后的24小时内以及成年后的24小时内。在这里，我们建议使用良好的寡核苷酸微阵列（Affymetrix）和最先进的分析方法状态来定义损伤引起的基因表达的改变。我们测定脊髓腰椎的背角作为模型系统，这主要是由于损伤引起的脊髓功能和神经生物学的短期变化和长期变化。我们在3至21天大的时候测试大鼠幼崽，并评估侮辱24小时后四次的基因表达变化。这描述了基因表达的更直接变化是损伤的函数。第二系列研究检查了开发早期不同年龄受伤的幼崽成年脊髓中基因表达的变化。在推定的关键时期，在生命的前两周，幼犬注入了角叉菜胶。较旧的幼崽经过测试，因为它们不在关键时期。被视为幼崽的成年人再次测试，无论有没有侮辱，基因表达都由微阵列测定。这些实验的结果将详细定义，当伤害性过程与成年人明显不同时，在发育早期引起的基因表达的变化，以及在关键时期结束后的发育后期再次引起。此外，我们描述了表达的长期变化，这可能解释了早期受伤引起的疼痛感知的“永久性”变化。这些数据将提供理性治疗的基础，这些治疗可能会减少过早和重病的婴儿对疼痛经历的任何有害影响。