Vision loss in elderly Veterans from age-related eye diseases such as Age-Related Macular Degeneration or Retinitis Pigmentosa is a significant cause of morbidity. The cellular and molecular signaling pathways in the eye that maintain normal retinal function and the mechanisms by which aging compromises their functions to cause retinal degeneration are poorly understood. Our long-term objective is to decipher the mechanisms required for normal retinal function and to identify how disruption of these mechanisms contributes to vision loss during aging. We have recently discovered that patients lacking Activating Transcription Factor 6 (ATF6) develop age-related vision loss. ATF6 encodes a key transcriptional regulator of cellular responses to endoplasmic reticulum and oxidative stress. The precise functions of ATF6 in normal retinal development, in survival of photoreceptors and retinal pigment epithelium during aging, and in development of age-related vision loss are unknown. Our central hypothesis is that ATF6 plays a key role in photoreceptor and retinal pigment epithelial cell function and viability. Guided by this hypothesis, we propose the following Specific Aims:
Aim #1. Determine the role of ATF6 in retinal pathology. ATF6 knockout mice develop age-related vision loss by unknown mechanisms. ATF6 is important for cells to survive oxidative and endoplasmic reticulum stresses, and we will analyze retinal phenotypes in ATF6 knockout mouse to see if stress responses are abnormal in the retina. In particular, we will focus on photoreceptor and Retinal Pigment Epithelial (RPE) cells because these are two cell types that are essential for vision and are highly sensitive to environmental or pathologic stresses. Death of these cells also causes many age- related retinal diseases.
Aim #2. Examine the role of ATF6 in age-related retinal degeneration and vision loss. We will use novel chemical and genetic tools to artificially activate the ATF6 signaling pathway in the eye after intraocular injection into the vitreous or sub-retina. We will test if artificial ATF6 signaling using these chemical or genetic tools can prevent age-related retinal degeneration and vision loss in an animal model of retinal degeneration that develops because of excessive oxidative and endoplasmic reticulum stress in photoreceptors.
Aim #3. Characterize the function of human ATF6 mutations linked to vision loss. We have identified mutations in ATF6 that are associated with vision loss in patients. It is unclear how these mutations affect ATF6 protein function and why mutant ATF6 bearing these mutations causes vision loss. We will perform site-directed mutagenesis and in vitro studies to characterize the biochemical and functional properties of mutant ATF6. In parallel, we will investigate how cells bearing mutant ATF6 tolerate and survive oxidative and endoplasmic reticulum stress. The significance of these studies is that they will decipher the role of ATF6 in retinal survival and in retinal degeneration. These studies will positively impact patient care at the VA by defining new molecular pathways that can be targeted to treat the underlying causes of vision loss in aging Veterans.
Over one million Veterans today cannot perform basic daily activities due to vision loss. These figures are expected to increase as more Veterans from the Korean and Vietnam conflict eras develop vision loss due to age-related damage to the retina. There are few treatments to prevent retinal degeneration because the mechanisms that maintain retinal homeostasis in response to environmental stresses are poorly understood. Oxidative and endoplasmic reticulum stress underlie the development of many age-related diseases. This VA merit application investigates the role of a major molecular regulator of oxidative and endoplasmic reticulum stress response, Activating Transcription Factor 6, in retinal survival and degeneration. This research may identify new molecular pathways that can be therapeutically targeted to prevent vision loss in aging Veterans.