Genetic Factors Affecting Aging of the Retina

描述（由申请人提供）：年龄依赖性疾病以年龄依赖性的方式表现，其致病机制与随着年龄增长而发生的细胞变化之间必须有密切的联系。因此，了解衰老过程是如何在分子水平上调控的，以及衰老过程如何与疾病机制相关联是很重要的。视网膜由于其组织良好的分层结构，为定量监测神经元组织的年龄依赖性变化提供了一个很好的模型。最近对小鼠和人类的研究表明，正常老化的视网膜会发生病变，包括异位感光突触的形成和感光细胞的逐渐变性。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衰老的理解。通过时间过程研究，我们发现C57BL/6J和a /J两种近交系小鼠视网膜年龄依赖性异常的严重程度不同，提示存在影响视网膜年龄依赖性异常的遗传因素。这种菌株差异使我们能够采用正向遗传学方法，这为识别以前不知道的调节视网膜衰老过程的基因和分子途径提供了潜力。这些基因/分子将成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，命名为视网膜老化rta1和rta2。通过充分利用现有的小鼠遗传资源，我们建议有效地精细定位和鉴定影响视网膜年龄依赖性异常严重程度的rta1和rta2基因。rta基因可能参与视网膜氧化应激的调节，氧化应激通常被认为是衰老过程的主要因素。这项研究的成功完成可能会证明这种遗传方法的可行性，它可以潜在地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。

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.