Defining the interplay of interferon-gamma and cathepsin S in age-related dry eye

定义干扰素-γ 和组织蛋白酶 S 在年龄相关性干眼症中的相互作用

• 批准号: 10703450
• 负责人: CINTIA S. DE PAIVA
• 金额: $ 37.49万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703450
• 关键词: 1 year old; Adenoviruses; Adoptive Transfer; Affect; Age; Aging; American; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Autoimmunity; Automobile Driving; Biological Assay; CD4 Positive T Lymphocytes; Cathepsins; Cell Separation; Cell physiology; Cells; Chronic; Chronology; Clinical; Colitis; Computers; Cornea; Cysteine; Data; Dendritic Cells; Desiccation; Development; Diet; Disease; Dry Eye Syndromes; Epithelial Cells; Epithelium; Frequencies; Generations; Goals; Goblet Cells; Health; Histologic; Immune; Immune system; Immunodeficient Mouse; Immunologic Deficiency Syndromes; In Vitro; Inflammaging; Inflammation; Inflammatory; Interferon Type II; Lacrimal gland structure; Lead; Life Expectancy; Lupus Nephritis; Lymphocytic Infiltrate; Measures; Mediating; Messenger RNA; Modeling; Mus; Ovalbumin; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Population; Pre-Clinical Model; Process; Production; Proteins; Randomized; Role; Sjogren' s Syndrome; Splenocyte; Stains; Stress; Testing; Th1 Cells; Vision; Wild Type Mouse; age related; aged; autoreactive T cell; autoreactivity; carboxypeptidase C; cytokine; experimental study; eye dryness; human old age (65+); improved; in vivo; inhibitor; ocular surface; paracrine; prevent; systemic inflammatory response

With increased life expectancy, debilitating diseases that accompany aging are also expected to rise, and one of them is dry eye disease. Increased age has repeatedly been associated with dry eye, although the precise mechanisms by which aging predisposes to dry eye disease remain unknown. Aging is accompanied by clinical, and sometimes sub-clinical chronic inflammation on the ocular surface and lacrimal gland (LG). The impact of age related dry eye disease is significant because it affects functional vision, as well as mobility, independence and the ability to perform daily tasks. Cathepsin S is a potent cysteine/protease expressed in the lysosomal compartments of both dendritic cells and LG acinar epithelia. Cathepsin S participates in physiological MHC II antigen presentation. Elevated levels of cathepsin S have been described in animal models and patients with Sjögren Syndrome and also in other animal models of autoimmunity, where it is thought to facilitate generation of autoreactive CD4+ T cells. Our preliminary data suggests that Cathepsin S is elevated in aging. However, the specific role of cathepsin S in the aged ocular surface and LG has not been elucidated. We hypothesize that age-related inflammatory changes in the ocular surface and LG lead to increased activity and production of cathepsin S by acinar epithelia and dendritic cells. This increased cathepsin S may 1) act in a paracrine fashion to amplify local inflammation and secretion of cytokines by the epithelium that can further increase cathepsin S creating a vicious circle; and 2) increase MHC II antigen presentation by aged dendritic cells, skewing them to prime pathogenic CD4+IFN-γ+ (Th1) cells that promote development of age-related dry eye disease. To investigate our hypothesis, we propose three specific aims: Specific Aim 1: how age-related inflammation in the ocular surface and LG stimulates cathepsin S production that promotes development of dry eye? Specific Aim 2: how age- related increase of cathepsin S modulates dendritic cell function and promotes the generation of autoreactive, pathogenic Th1 cells? Specific Aim 3: can cathepsin S inhibition modulate age-related dry eye? Results from these proposed experiments will improve our understanding of the fundamental mechanisms of age-related dry eye disease. Furthermore, it will change our view of aging on the ocular surface from an inevitable passive, degenerative process to an active, inflammatory and immune- mediated status that can be targeted, thus opening venues to prevent deleterious age-related dry eye.

随着预期寿命的增加，伴随衰老的衰弱性疾病预计也会增加， 其中之一就是干眼症。年龄的增长一再与干眼症有关， 尽管衰老易患干眼病的确切机制仍不清楚。 衰老伴随着眼部的临床，有时是亚临床慢性炎症 表面和泪腺（LG）。与年龄相关的干眼症的影响是显著的，因为它 影响功能性视力，以及移动性，独立性和执行日常任务的能力。 组织蛋白酶S是一种有效的半胱氨酸/蛋白酶，在两种树突状细胞的溶酶体区室中表达。 细胞和LG腺泡上皮。组织蛋白酶S参与生理性MHC II抗原呈递。 组织蛋白酶S水平升高已在动物模型和干燥综合征患者中描述 综合征，也在其他动物模型的自身免疫，其中它被认为是促进产生 自身反应性CD 4 + T细胞。我们的初步数据表明，组织蛋白酶S在衰老中升高。 然而，组织蛋白酶S在老年眼表和LG中的具体作用尚未阐明。 我们假设年龄相关的眼表炎症变化和LG导致 腺泡上皮细胞和树突状细胞的组织蛋白酶S的活性和产量增加。这种增加的 组织蛋白酶S可能1）以旁分泌方式起作用以放大局部炎症和细胞因子分泌 通过上皮细胞，可以进一步增加组织蛋白酶S，产生恶性循环; 2）增加MHC 老化树突状细胞的II型抗原呈递，使其倾向于引发致病性CD 4 +IFN-γ+（Th 1） 促进与年龄相关的干眼病发展的细胞。为了研究我们的假设，我们 提出了三个具体目标：具体目标1：如何在眼表年龄相关的炎症， LG刺激组织蛋白酶S的产生，促进干眼症的发展？具体目标2：如何年龄- 相关的组织蛋白酶S的增加调节树突状细胞的功能，并促进树突状细胞的产生。 自身反应性致病性Th 1细胞具体目标3：组织蛋白酶S抑制是否可以调节年龄相关的 干眼？这些实验的结果将提高我们对基本原理的理解。 与年龄相关的干眼症的发病机制。此外，它将改变我们对眼部衰老的看法， 从一个不可避免的被动的、退化的过程转变为一个主动的、炎症的和免疫的过程， 介导的状态，可以有针对性的，从而打开场地，以防止有害的年龄相关的干眼。