| The aldehyde dehydrogenase (ALDH) gene superfamily is a group of evolutionarily-related, nicotinamide adenine dinucleotide-dependent enzymes responsible for the oxidation of numerous physiologic and pathophysiologic substrates within all biological systems. This thesis will focus on a) the characterization of two members within this superfamily in the protection against the ubiquitous byproduct of oxidative stress-induced membrane peroxidation, 4-hydroxy-2-nonenal (4-HNE) and b) a web-publishing system designed for reporting on the ALDH gene superfamily as a whole.;We begin with a review of 4-HNE and the mechanisms within the ocular tissues responsible for the metabolism and disposition of this aldehyde. This aldehyde's intracellular level appears to be regulated by several biotransformative pathways involving reduction, oxidation and conjugation. Herein we discuss the members involved in these pathways and their relative presence within the ocular tissues.;In the next chapter, we investigate the protective roles of two ALDHs highly expressed in mammalian corneal tissues (ALDH1A1 and ALDH3A1) against 4-HNE-induced cytotoxicity. Both enzymes have reported activity for 4-HNE and may be integrally involved in its oxidative biotransformation. The results of these studies clearly demonstrate that ALDH3A1 plays a significant role in limiting the cytotoxic events associated with 4-HNE exposure and further clarifies this enzyme's role in the maintenance of intracellular redox balance.;In the fourth chapter, we describe the development of a publicly available, relational-database resource for web-based publishing of the ALDH gene superfamily. The top-down approach to data curation by the major institutions has been invaluable, however, due to substantial reliance on automated curatorship, a bottom-up approach to curation and data distillation is also necessary. Here we describe our solution to this approach, the ALDH Gene Superfamily Resource Database (ALDH GSRD) hosted at www.aldh.org.;In the final chapter, we investigate, classify and report the human alternatively-spliced transcriptional variants for members of the ALDH gene superfamily. Here we provide evidence for this variation for each member as well as an HGNC-based recommended nomenclature system to describe these variants. We anticipate that further investigation of these splice variants at the lab bench will provide valuable insight to our understanding of their physiological relevance and etiology in pathological processes. |
