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 这是对性别/性别影响研究的行政补充的应用程序（Not-OD-20-- 049）。母体R01（5R01EY030072-02）的总体目标是调查弹性酶和 视网膜色素上皮功能（RPE）和健康中的弹性蛋白片段，以及如何在 弹性酶抑制剂Alpha-1抗trypsin（A1-AT）的存在。父母赠款的总体假设是 年龄和/或应力依赖性弹性酶活性的增加，导致弹性蛋白降解并协调 （抗）α-雌激素抗体的产生是AMD的早期EVENS。由于AMD是一种患病率更高的疾病 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会有所不同，从而导致AMD差异 发展。因此，我们建议在AMD鼠标模型中使用增加的样本量作为残留 退化，以及对回顾性患者数据库的其他分析，以衡量差异 在性之间。我们已经开发了三个特定的目标来完成父母的赠款，从而允许 分析AMD病理生物学中性别的生物学差异。第一个目标将表征性别差异 弹性蛋白更新，α-丙都是抗体的产生和ADCC的证据（抗体依赖性细胞） 残留变性的小鼠模型中的细胞毒性）和CDC（补体依赖性细胞毒性）。这 第二个目的将检验以下假设：雌性小鼠中α-丙都是抗体增加了 RPE损伤的小鼠模型中的病理学。对于特定目标3，我们将测试A1-AT治疗的假设 导致人和小鼠受试者AMD发作的性别差异。目标1-3将使用实验 在父母赠款中提出的，以进一步探索结构，功能和基因表达的差异 在性之间。为了分析在A1-AT治疗存在下AMD发作的性别差异，我们将 分析市场扫描数据库中男性和女性之间的差异。这种赠款补充剂将 提供有关性如何影响AMD病理差异的急需知识。这个新颖的数据将有助于 在开发AMD疗法的过程中，并提供了开发更个性化的信息 卫生保健的方法，考虑性别之间的差异。