Genetic Factors Affecting Aging of the Retina

影响视网膜老化的遗传因素

• 批准号: 8586265
• 负责人: AKIHIRO IKEDA
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586265
• 关键词: Affect; Aging; Aging-Related Process; Alleles; Candidate Disease Gene; Chromosome Mapping; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 7; Consomic Strain; Data; Disease; Genes; Genetic; Goals; Human; Inbred Strains Mice; Link; Maps; Mediator of activation protein; Modeling; Molecular; Monitor; Mus; Names; Neurons; Oxidative Stress; Pathway interactions; Phenotype; Photoreceptors; Recombinant Inbred Strain; Recombinants; Regulation; Research; Resistance; Resources; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Severities; Structure; Synapses; Testing; Time; Tissues; Transcript; age related; aging gene; base; consomic; forward genetics; genetic resource; normal aging; photoreceptor degeneration; public health relevance; response

DESCRIPTION (provided by applicant): For age-dependent diseases to manifest themselves in an age-dependent manner, there must be tight association between the disease-causing mechanisms and cellular changes that occur with aging. Therefore, it is important to understand how aging process is regulated at the molecular level, and how aging process is associated with disease mechanisms. The retina offers an excellent model to quantitatively monitor age- dependent changes in the neuronal tissue due to its well-organized layered structure. Recent studies in mice and humans have shown that the normal aging retina goes through pathological changes including the formation of ectopic photoreceptor synapses and gradual photoreceptor cell degeneration. Similar retinal abnormalities are observed in age-dependent retinal degenerative diseases as well. Elucidating the molecular mechanisms causing the common age-dependent retinal abnormalities, therefore, should enhance our understanding of age-dependent retinal diseases and aging of the retina. Through a time-course study, we found that the severity of age-dependent abnormalities in the retina differs between two inbred strains of mice, C57BL/6J and A/J, indicating the existence of genetic factor(s) affecting age-dependent abnormalities in the retina. This strain difference allows us to employ the forward genetics approach, which offers potential to identify genes and molecular pathways that were not previously known to regulate the aging process in the retina. Such genes/molecules will serve as new entry points to understand the molecular networks that are affected by retinal aging. We have identified two major chromosomal loci affecting the severity of age-dependent synaptic abnormality, named retinal aging rta1 and rta2. By taking full advantage of available mouse genetics resources, we propose to efficiently fine map and identify rta1 and rta2 genes that influence the severity of this age-dependent abnormality in the retina. The rta genes may be involved in the retinal regulation of oxidative stress, which is considered a major contributor to the aging process in general. Successful completion of the proposed research may prove the feasibility of this genetic approach, which can be potentially applied to a larger study to identif genes regulating other aspects of retinal aging.

描述（由申请人提供）：对于以年龄依赖性方式表现出来的年龄依赖性疾病，致病机制与随衰老而发生的细胞变化之间必须存在紧密关联。因此，了解衰老过程如何在分子水平上受到调控以及衰老过程与疾病机制的关系非常重要。由于其组织良好的分层结构，视网膜提供了一个很好的模型来定量监测神经元组织的年龄依赖性变化。最近对小鼠和人类的研究表明，正常老化的视网膜会经历病理变化，包括异位感光突触的形成和逐渐感光细胞退化。在年龄依赖性视网膜退行性疾病中也观察到类似的视网膜异常。因此，阐明导致常见的年龄依赖性视网膜异常的分子机制应该增强我们对年龄依赖性视网膜疾病和视网膜老化的理解。 通过时间过程研究，我们发现两种近交系小鼠 C57BL/6J 和 A/J 视网膜年龄依赖性异常的严重程度不同，表明存在影响年龄依赖性异常的遗传因素在视网膜中。这种应变差异使我们能够采用正向遗传学方法，该方法提供了识别以前未知的调节视网膜衰老过程的基因和分子途径的潜力。这些基因/分子将作为了解受视网膜老化影响的分子网络的新切入点。我们已经确定了影响年龄依赖性突触异常严重程度的两个主要染色体位点，称为视网膜老化 rta1 和 rta2。通过充分利用可用的小鼠遗传资源，我们建议有效地精细绘制图谱并识别影响这种年龄依赖性视网膜异常严重程度的 rta1 和 rta2 基因。 rta 基因可能参与视网膜氧化应激的调节，氧化应激被认为是衰老过程的一个主要因素。拟议研究的成功完成可能会证明这种遗传方法的可行性，该方法有可能应用于更大规模的研究，以确定调节视网膜衰老其他方面的基因。