The long term goal of this project is to elucidate the role of aldehyde dehydrogenases (ALDH3A1 and ALDH1A1) in the ocular defense mechanism against ultraviolet radiation (UVR) toxicity. It is well known that UVR induces reactive oxygen species (ROS) that leads to membrane lipid peroxidation and accumulation of toxic aldehydes, such as 4-hydroxy-2- nonenal (4-HNE). Both ALDH3A1 and ALDH1A1 detoxify 4-HNE, which has been implicated in the pathogenesis of several diseases including cataract and degenerative retinal disease. During the last funding period, we have made novel and significant discoveries regarding the protective role of ALDH3A1 and ALDH1A1 against ocular oxidative stress. We found that both enzymes protect against UVR- and 4-HNE-induced cellular toxicity, and that, at least ALDH3A1, may act as UVR filter protecting other enzymes from inactivation. Finally, and most importantly, we found that Aldh3a1(-/-) and Aldh1a1(-/- )/Aldh3a1(-/-) knockout mice develop anterior and posterior subcapsular cataracts early in life, whereas Aldh1a1(-/-) knockout animals develop cataracts later in life. These novel data support our working hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via non-enzymatic (light filtering) and enzymatic (detoxification) functions. The experiments proposed in this competitive renewal application continue our systematic approach to characterizing the role of corneal ALDH3A1 and lens ALDH1A1 in the protection against UVR- induced eye pathologies. In the next 5 years, we propose to:
Specific Aim 1 : To distinguish the physiological functions of non-enzymatic (light filtering) from enzymatic (detoxification) functions of ALDH3A1 and ALDH1A1 by developing Aldh3a1 and Aldh1a1 knock-in mouse lines that express enzymatically- inactive proteins. The ocular phenotypes of these knock-in mouse models will be compared to that of the Aldh3a1(-/-) and Aldh1a1(-/-) knockout mice and wild-type animals Specific Aim 2: Examine the hypothesis that novel and selective small molecule activators of ALDH1A1 and ALDH3A1 will protect the eye against UVR-induced pathologies. Following administration of these activators and exposure to UVR, corneal injury and cataract formation will be studied in parallel with formation and characterization of 4-HNE-adducted proteins in wild-type and Aldh-knockout mice.
Specific Aim 3 : Evaluate the hypothesis that ALDH3A1 and ALDH1A1 protect the retina. The protective effects of both ALDH3A1 and ALDH1A1 will be determined by identifying aging- and UVR-induced biochemical and histological changes in the retina of Aldh3a1(-/-), Aldh1a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) single and double knockout mouse lines. These studies will provide valuable data on (a) the role and the molecular mechanisms of the ocular ALDH1A1 and ALDH3A1 in protecting the eye from UVR-induced oxidative damage and (b) drug development that may be used to prevent eye pathologies. It is anticipated that the information gleaned from these studies will lead to novel approaches for the prevention and treatment of eye diseases in the human population.
Relevance of this research to public health: It is well documented that ultraviolet radiation (UVR) causes eye pathologies in cornea, lens and retina. Opacification of the lens, known as cataract, is the leading cause of blindness in the world. Cornea and lens contain some proteins, namely aldehyde dehydrogenases (ALDH1A1 and ALDH3A1), that protect against UVR-induced cataract formation and corneal pathologies. The proposed research will characterize the role and the molecular mechanisms of ocular ALDH1A1 and ALDH3A1 in protecting the eye from UVR-induced damage, and will serve as a foundation for future drug development.
|Koppaka, Vindhya; Chen, Ying; Mehta, Gaurav et al. (2016) ALDH3A1 Plays a Functional Role in Maintenance of Corneal Epithelial Homeostasis. PLoS One 11:e0146433|
|Singh, Surendra; Arcaroli, John J; Orlicky, David J et al. (2016) Aldehyde Dehydrogenase 1B1 as a Modulator of Pancreatic Adenocarcinoma. Pancreas 45:117-22|
|Monte, Andrew A; Heard, Kennon J; Hoppe, Jason A et al. (2015) The accuracy of self-reported drug ingestion histories in emergency department patients. J Clin Pharmacol 55:33-8|
|Singh, S; Arcaroli, J; Thompson, D C et al. (2015) Acetaldehyde and retinaldehyde-metabolizing enzymes in colon and pancreatic cancers. Adv Exp Med Biol 815:281-94|
|Jackson, Brian C; Reigan, Philip; Miller, Bettina et al. (2015) Human ALDH1B1 polymorphisms may affect the metabolism of acetaldehyde and all-trans retinaldehyde--in vitro studies and computational modeling. Pharm Res 32:1648-62|
|Monte, Andrew A; Anderson, Peter; Hoppe, Jason A et al. (2015) Accuracy of Electronic Medical Record Medication Reconciliation in Emergency Department Patients. J Emerg Med 49:78-84|
|Heit, Claire; Dong, Hongbin; Chen, Ying et al. (2015) Transgenic mouse models for alcohol metabolism, toxicity, and cancer. Adv Exp Med Biol 815:375-87|
|Monte, Andrew A; Heard, Kennon J; Campbell, Jenny et al. (2014) The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med 21:879-85|
|Jang, Jun-Ho; Bruse, Shannon; Liu, Yushi et al. (2014) Aldehyde dehydrogenase 3A1 protects airway epithelial cells from cigarette smoke-induced DNA damage and cytotoxicity. Free Radic Biol Med 68:80-6|
|Ioannou, Marilia; Serafimidis, Ioannis; Arnes, Luis et al. (2013) ALDH1B1 is a potential stem/progenitor marker for multiple pancreas progenitor pools. Dev Biol 374:153-63|
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