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: 10231017
• 负责人: CINTIA S. DE PAIVA
• 金额: $ 43.03万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231017
• 关键词: 1 year old; Address; Adenoviruses; Adoptive Transfer; Affect; Age; Aging; American; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Autoimmunity; Automobile Driving; Biological Assay; CD4 Positive T Lymphocytes; Caspase; Cathepsins; Cell physiology; Chronic; Chronology; Clinical; Colitis; Computers; Cornea; Data; Dendritic Cells; Development; Diet; Disease; Dry Eye Syndromes; Epithelial; Epithelial Cells; Frequencies; G Cells; Generations; Goals; Goblet Cells; Health; Histologic; Immune; Immune system; Immunodeficient Mouse; In Vitro; Infiltration; Inflammaging; Inflammation; Inflammatory; Interferon Type II; Lacrimal gland structure; Lead; Life Expectancy; Lupus Nephritis; Lymphocyte; Measures; Mediating; Messenger RNA; Modeling; Mus; Ovalbumin; Pathogenicity; Pathway interactions; Patients; 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/antagonist; 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，衰老伴随的衰弱疾病也有望增加， 其中之一是干眼症。年龄越来越多与干眼有关， 尽管衰老易于干眼症的确切机制尚不清楚。 衰老是通过临床上的，有时是临床上的慢性感染来完成的 表面和泪腺（LG）。与年龄相关的干眼病的影响很大，因为它 影响功能视觉，移动性，独立性和执行日常任务的能力。 组织蛋白酶S是一种潜在的半胱氨酸/蛋白酶，在两个树突状的溶酶体室中表达 细胞和LG腺泡上皮。组织蛋白酶在物理MHC II抗原表现中的参与者。 在动物模型和Sjögren患者中，已经描述了组织蛋白酶的水平升高 综合征以及其他自身免疫模型中，人们认为它有助于生成 自动反应性CD4+ T细胞。我们的初步数据表明，在衰老中，组织蛋白酶升高。 但是，尚未阐明组织蛋白酶在老化的眼表和LG中的特定作用。 我们假设眼表和LG与年龄相关的炎症变化导致 通过腺泡上皮和树突状细胞增加了组织蛋白酶的活性和产生。这增加了 组织蛋白酶5月1日）以旁分裂的方式起作用，以扩大局部炎症和细胞因子的分泌 通过上皮，可以进一步增加组织蛋白酶，从而创造出奇妙的圆圈； 2）增加MHC II抗原呈现年龄的树突状细胞，将它们偏向于原发致病性CD4+ IFN-γ+（TH1） 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 提案三个具体目的：特定目标1：眼表面与年龄相关的炎症如何 LG刺激组织蛋白酶的生产，从而促进干眼症的发育？特定目标2：年龄如何 关联组织蛋白酶的相关增加可调节树突状细胞功能，并促进产生 自动反应性，致病性Th1细胞？特定的目标3：组织蛋白酶的抑制作用可以调节与年龄相关的 干眼？这些提出的实验的结果将提高我们对基本的理解 与年龄相关的干眼病的机制。此外，它将改变我们对眼部衰老的看法 从不可避免的被动，退化过程到主动，炎症和免疫的表面 可以针对目标的介导状态，从而打开场地，以防止有害年龄相关的干眼。