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充申请（NOT-OD-20- 049）。亲本R 01（5 R 01 EY 030072 -02）的总体目标是研究弹性蛋白酶的作用， 弹性蛋白片段在视网膜色素上皮功能（RPE）和健康中的作用，以及它如何在视网膜色素上皮功能（RPE）中被修饰。 存在弹性蛋白酶抑制剂，α-1抗胰蛋白酶（A1-AT）。父母补助金的总体假设是 弹性蛋白酶活性年龄和/或压力依赖性增加导致弹性蛋白降解和协调 （抗）α-弹性蛋白抗体的产生是AMD的早期事件。由于AMD是一种患病率较高的疾病， 在女性中，我们进一步假设弹性蛋白酶活性可能因性别而异，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量，用于视网膜病变的研究。 退化，以及对回顾性患者数据库的额外分析，以测量差异 性之间。我们制定了三个具体目标，以补充父母补助金的目标， AMD病理生物学的性别生物学差异分析。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ADCC（抗体依赖性细胞免疫）的证据 细胞毒性）和CDC（补体依赖性细胞毒性）。的 第二个目标是检验雌性小鼠中的α-弹性蛋白抗体增加的假设。 在RPE损伤的小鼠模型中的病理学。对于具体目标3，我们将检验A1-AT治疗 导致人类和小鼠受试者中AMD发作的性别差异。目标1-3将利用实验 在父母补助金中提出，以进一步探索结构，功能和基因表达的差异 性之间。为了分析在A1-AT治疗的情况下AMD发病的性别差异，我们将 分析MarketScan数据库中男性和女性之间的差异。该补助金将 提供关于性别如何影响AMD病理差异的急需知识。这些新数据将有助于 在AMD治疗的发展，并提供所需的信息，以开发更个性化的治疗方法， 考虑到性别差异的保健方法。

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.