Sex and Gender Supplement to Elastase and Elastin Peptide Activity in Age-Related Macular Degeneration

摘要

ABSTRACT This is an application for an Administrative Supplement for Research on Sex/Gender Influences (NOT-OD-20- 049). The overall goals of the parent R01 (5R01EY030072-02) are to investigate the roles of elastase and elastin fragments in retina pigment epithelial function (RPE) and health, and how it may be modified in the presence of the elastase inhibitor, alpha-1 anti-trypsin (A1-AT). The overall hypothesis of the parental grant is that age- and/or stress-dependent increase in elastase activity leading to elastin degradation and coordinated production of (anti) α-elastin antibodies are early evens in AMD. As AMD is a disease with greater prevalence in females, we further hypothesize that elastase activity may vary between sex leading to differences in AMD development. Therefore, we propose to use increased sample size within an AMD mouse model for retinal degeneration, as well as additional analysis of a retrospective patient database to measure for differences between sex. We have developed three specific aims to complement those of the parental grant, allowing for analysis of biological differences of sex in AMD pathobiology. The first aim will characterize sex differences in elastin turnover, production of α-elastin antibodies and evidence of ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity) within a mouse model of retinal degeneration. The second aim will test the hypothesis that α-elastin antibodies in female mice have increased augmented pathology in a mouse model of RPE damage. For specific aim 3, we will test the hypothesis that A1-AT therapy results in sex-differences in onset of AMD in human and mouse subjects. Aims 1-3 will utilize experiments proposed in the parental grant to further explore differences in structure, function, and gene expression between sex. To analyze sex differences on the onset of AMD in the presence of A1-AT therapy, we will analyze differences between males and females in the MarketScan Database. This grant supplement will provide much needed knowledge on how sex may affect differences in AMD pathology. This novel data will aid in the development of AMD therapeutics and provide information needed to develop a more individualized approach to health care which considers differences between sex.