Our long-term goal is to understand the molecular mechanisms causing human diseases associated with aging. One possible mechanism for age-dependent diseases is acceleration of the aging process by environmental and genetic factors. Our previous studies show that mouse models showing accelerated aging phenotypes are powerful tools to identify such factors in the retina. An ENU-induced mutant mouse model, FUN025, displays accelerated retinal aging, as well as certain key pathologies observed in age-related retinal diseases including retinal pigment epithelium (RPE) cell abnormalities, inflammation and photoreceptor cell degeneration, suggesting that the responsible gene is involved in the regulation of retinal aging, and that its impairment leads to development of the age-dependent retinal abnormalities. In the previous funding period, we identified that a mutation in transmembrane protein 135 (Tmem135) is responsible for the retinal abnormalities in FUN025 mice. We found that TMEM135 localizes to mitochondria, and is involved in mitochondrial fission. Sensitivity to oxidative stress increases in cultured Tmem135 mutant cells and mutant retina, likely due to the mitochondrial abnormalities. Our observations indicate that the RPE is the primary site affected by the Tmem135 mutation. In addition, we found that over-expression of wild-type Tmem135 in mice results in RPE cell degeneration. Based on these findings, we hypothesize that proper control of mitochondrial dynamics through TMEM135 is essential to maintain normal function and integrity of RPE cells, dysregulation of which leads to age-dependent abnormalities. In addition to our own findings, there is increasing evidence to show that RPE is the target of age-dependent diseases including age-related macular degeneration. However, the etiology of RPE dysfunction/death in these age-related diseases is not well understood. In this renewal proposal, we will investigate how defective mitochondrial dynamics due to Tmem135 result in RPE dysfunction/degeneration. Specifically, we will 1) determine molecular pathways affected by Tmem135 mutation/over-expression in RPE cells, 2) study how mitochondrial dynamics affect the integrity and function of the RPE and how TMEM135 is involved in this process, and 3) identify genetic modifiers of RPE cell degeneration caused by Tmem135 overexpression. Successful completion of this project will reveal the role of mitochondrial dynamics and Tmem135 in age-dependent changes of RPE cells, and identify factors involved in those processes, which may lead to novel supplementation or treatment options for aging and age-related diseases in the retina.

Public Health Relevance

For age-dependent diseases to manifest themselves in an age-dependent manner, the process of aging and its associated cellular changes must play key roles. Using mouse models with accelerated retinal aging and age-related disease pathologies in the retina, we propose to determine the molecular mechanisms underlying theses conditions. This study may provide insights into how age-dependent retinal pathologies are caused and offer therapeutic strategies for prevention of retinal conditions associated with aging and age-dependent retinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022086-06
Application #
9975162
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2012-08-01
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Genetics
Type
Earth Sciences/Resources
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Lewis, Sarah Aileen; Takimoto, Tetsuya; Mehrvar, Shima et al. (2018) The effect of Tmem135 overexpression on the mouse heart. PLoS One 13:e0201986
Bhute, Vijesh J; Bao, Xiaoping; Dunn, Kaitlin K et al. (2017) Metabolomics Identifies Metabolic Markers of Maturation in Human Pluripotent Stem Cell-Derived Cardiomyocytes. Theranostics 7:2078-2091
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
Maddox, Dennis M; Collin, Gayle B; Ikeda, Akihiro et al. (2015) A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Invest Ophthalmol Vis Sci 56:3776-87