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

摘要 这是一份关于性/性别影响研究的行政补助金的申请(非-OD-20- 049)。亲本R01(5R01EY030072-02)的总体目标是研究弹性蛋白酶和 弹性蛋白片段在视网膜色素上皮功能(RPE)和健康中的作用，以及如何在 弹性酶抑制剂α-1抗胰蛋白酶(A1-AT)的存在。父母助学金的总体假设是 这种年龄和/或压力依赖性弹性蛋白酶活性增加导致弹性蛋白降解和协调 产生(抗)α-弹性蛋白抗体是老年性黄斑变性的早期事件。因为AMD是一种发病率更高的疾病 在女性中，我们进一步假设弹性蛋白酶活性在性别之间可能不同，从而导致AMD的差异。 发展。因此，我们建议在AMD小鼠模型中使用增加的样本大小来研究视网膜 变性，以及对回溯性患者数据库的额外分析，以衡量差异 在性爱之间。我们制定了三个具体目标，以补充父母补助金的目标，允许 AMD病理生物学的性别差异分析。第一个目标将描述性别差异 弹性蛋白周转、α-弹性蛋白抗体的产生和抗体依赖细胞的证据 (细胞毒性)和CDC(补体依赖细胞毒性)在小鼠视网膜变性模型中。这个 第二个目标将检验这样的假设，即雌性小鼠中的α-弹性蛋白抗体增加了 视网膜色素上皮损伤小鼠模型的病理学研究。对于特定的目标3，我们将检验A1-AT疗法的假设 导致人类和小鼠AMD发病的性别差异。AIMS 1-3将利用实验 在父母资助中提出，进一步探索结构、功能和基因表达的差异 在性爱之间。为了分析A1-AT治疗中AMD发病的性别差异，我们将 在MarketScan数据库中分析男性和女性之间的差异。这项赠款补充将 就性别如何影响AMD病理差异提供亟需的知识。这一新颖的数据将有助于 在AMD治疗学的发展中，并提供所需的信息，以开发更个性化的 考虑到性别差异的医疗保健方法。

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.