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

年龄相关性黄斑变性中弹性蛋白酶和弹性蛋白肽活性的性别和性别补充

• 批准号: 10334019
• 负责人: Baerbel Rohrer
• 金额: $ 15.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334019
• 关键词: Accounting; Administrative Supplement; Affect; Age of Onset; Age related macular degeneration; Antibodies; Antibody Formation; Biological; Blindness; Bruch' s basal membrane structure; Centers for Disease Control and Prevention (U.S.); Complement; Complement Activation; Complement-Dependent Cytotoxicity; Data; Data Analyses; Data Set; Databases; Development; Diagnosis; Disease; Disease Progression; Elastases; Elastin; Event; Exhibits; Extracellular Matrix; Eye; Female; Gender; Gene Expression; Goals; Grant; Health; Healthcare; Human; Immune response; Inflammatory; Intraperitoneal Injections; Knowledge; Measures; Modeling; Mus; Oxidative Stress; Parents; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Peptides; Prevalence; Production; Pulmonary Emphysema; Research; Retinal Degeneration; Risk; Role; Sample Size; Serine Protease; Sex Differences; Stress; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Therapeutic Effect; Thinness; Transgenic Mice; Trypsin; United States; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; antibody-dependent cell cytotoxicity; base; biological sex; elastase inhibitor; experimental study; inhibitor/antagonist; male; mouse model; novel; personalized approach; response; sex; tool

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.

抽象的 这是性别/性别影响研究行政补充申请（NOT-OD-20- 049) 母体 R01 (5R01EY030072-02) 的总体目标是研究弹性蛋白酶和 弹性蛋白片段对视网膜色素上皮功能 (RPE) 和健康的影响，以及如何对其进行修改 弹性蛋白酶抑制剂 α-1 抗胰蛋白酶 (A1-AT) 的存在 父母资助的总体假设是。 弹性蛋白酶活性的年龄和/或压力依赖性增加导致弹性蛋白降解并协调 （抗）α-弹性蛋白抗体的产生是 AMD 的早期事件，因为 AMD 是一种患病率较高的疾病。 在女性中，我们进一步发现弹性蛋白酶活性可能因性别而异，从而导致 AMD 的差异 因此，我们建议在 AMD 小鼠视网膜模型中使用更大的样本量。 退化，以及对回顾性患者数据库进行额外分析以衡量差异 我们制定了三个具体目标来补充父母补助金的目标，并考虑到 AMD 病理学中性别生物学差异的分析 第一个目标是表征 AMD 病理学中的性别差异。 弹性蛋白周转、α-弹性蛋白抗体的产生以及 ADCC（抗体依赖性细胞 视网膜变性小鼠模型中的细胞毒性）和 CDC（补体依赖性细胞毒性）。 第二个目标将检验雌性小鼠体内 α-弹性蛋白抗体增加的假设 RPE 损伤小鼠模型的病理学 对于特定目标 3，我们将检验 A1-AT 疗法的假设。 目标 1-3 将利用实验得出人类和小鼠受试者 AMD 发病的性别差异。 在父母资助中提出探索结构、功能和基因表达的进一步差异 为了分析 A1-AT 治疗下 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。 提供有关性别如何影响 AMD 病理学差异的急需知识。这些新颖的数据将有所帮助。 参与 AMD 疗法的开发，并提供开发更个性化治疗所需的信息 考虑性别差异的医疗保健方法。