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.

Public Health Relevance

The similarity of retinal abnormalities observed in aging and age-dependent retinal diseases suggests the link between molecular mechanisms underlying these conditions. By taking full advantage of available mouse genetics resources, we propose to efficiently identify genetic factors that influence the severity of age- dependent abnormality in the retina. This study will provide entry points into the molecular mechanisms regulating the aging process in the retina, which may also help us understand how age-dependent retinal diseases are caused.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (DPVS)
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Shen, Grace L
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University of Wisconsin Madison
Schools of Medicine
United States
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Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae et al. (2016) Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies. Elife 5:
Higuchi, Hitoshi; Macke, Erica L; Lee, Wei-Hua et al. (2015) Genetic basis of age-dependent synaptic abnormalities in the retina. Mamm Genome 26:21-32