Optic-nerve-head (ONH) Chips for Glaucomatous Neurodegeneration

用于治疗青光眼神经变性的视神经头 (ONH) 芯片

• 批准号: 10439107
• 负责人: Yong Yang
• 金额: $ 46.32万
• 依托单位: UNIVERSITY OF NORTH TEXAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439107
• 关键词: 3-Dimensional; Accreditation; African American; Age; Anatomy; Area; Astrocytes; Axon; Biocompatible Materials; Biomechanics; Biomedical Engineering; Biomimetics; Blindness; Cell physiology; Characteristics; Coculture Techniques; Consumption; Development; Disease; Engineering; Event; Eye; Foundations; Functional disorder; Future; Glaucoma; Health; Hispanic; Human; In Situ; In Vitro; Incidence; Interdisciplinary Study; Investigation; Lead; Link; Mechanics; Minority Women; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Ocular Hypertension; Optic Disk; Optic Nerve; Organ; Pathogenesis; Pathologic; Physiologic Intraocular Pressure; Physiological; Radial; Research; Research Institute; Retinal Ganglion Cells; Risk Factors; Students; System; Technology; Texas; Therapeutic; Time; Underrepresented Minority; Vision; Vitreous Chamber; Woman; Yang; axon injury; base; career; cost; cost effective; design; efficacious treatment; in vitro Model; in vivo; innovation; insight; mechanical stimulus; mechanotransduction; mouse model; nanoengineering; neuroprotection; novel; organ on a chip; polydimethylsiloxane; pressure; prognostic; programs; prototype; response; retinal damage; retinal ganglion cell degeneration; undergraduate student

While there is a continuous increase in the incidence of glaucoma, the leading cause of irreversible blindness worldwide, current glaucoma therapies show limited efficacy. As the most prominent causative and prognostic risk factor of glaucoma, elevated intraocular pressure (IOP) could deform the optic nerve head (ONH) and damage the retinal ganglion cell (RGC) axons as they pass through the ONH. Current glaucoma therapies focus on lowering IOP, yet the vision loss continues over time despite a well-controlled IOP. Extensive evidence suggests the ONH astrocyte response to elevated IOP as a mechanism for RGC axonal damage. The astrocytes express mechanosensitive channels, sense the mechanical deformation, and become reactive in response to IOP elevation, which may lead to pathological changes of glaucoma. However, the effects of IOP on ONH biomechanics are not fully understood. Of note, the ONH stiffness changes with age, glaucoma and IOP elevation, and the astrocytes are highly sensitive to microenvironment stiffness and mechanical stimuli. While widely used mouse models are costly, time-consuming and facility limited, most of conventional in vitro ONH models are based on 2-D stiff substrates without incorporating key anatomical and physiological characteristics of native ONH, leading to cellular processes deviated from the in vivo events. We thus hypothesized that the ONH model that closely resembles the physical and mechanical characteristics of native ONH will allow more accurate in vitro glaucoma study. Therefore, the objective of this project is to develop ONH-on-a-chip systems that recapitulate the key structural (co-culture of astrocytes and RGCs), physical (radial aligned RGCs and matrix stiffness), and mechanical (IOP) characteristics of native ONH to delineate the astrocytic mechanisms of glaucoma pathogenesis. An interdisciplinary research team has been assembled to have expertise in organ-on-a-chip technology, glaucoma neurodegeneration, biomechanics and biomaterials, and two Specific Aims are proposed: (1) engineer and validate ONH chips of pathophysiological relevance, and (2) delineate mechanosensing mechanisms underlying glaucoma pathogenesis on the chips. Successful completion of this project will deliver novel, biomimetic ONH chips to provide a reliable, rapid, and inexpensive model to delineate the glaucomatous neurodegeneration. The validated mouse ONH chips will lay the foundation for developing human ONH chip to advance the mechanistic understanding of glaucoma pathogenesis and facilitate the development of disease-modifying therapeutic approaches. The Department of Biomedical Engineering at UNT has a newly ABET-accredited undergraduate program with approximately 254 students (117 women, Hispanic = 77, African American = 33) in 2020. The proposed AREA program will provide research opportunity to undergraduate students, particularly for underrepresented minority and female students and motivate them to pursue their future career in biomedical and health-related areas.

虽然青光眼的发病率持续增加，但它是不可逆转的主要原因 在全球范围内导致失明，目前的青光眼疗法效果有限。作为最突出的致病因素和 青光眼的预后危险因素，眼内压（IOP）升高可能导致视神经乳头变形 (ONH) 并在视网膜神经节细胞 (RGC) 轴突通过 ONH 时损伤它们。目前青光眼 治疗的重点是降低眼压，但尽管眼压控制良好，但随着时间的推移，视力丧失仍在继续。 大量证据表明 ONH 星形胶质细胞对升高的 IOP 的反应是 RGC 轴突的机制 损害。星形胶质细胞表达机械敏感通道，感知机械变形，并成为 对眼压升高产生反应，可能导致青光眼的病理变化。然而， IOP 对 ONH 生物力学的影响尚未完全了解。值得注意的是，ONH 硬度随着年龄的增长而变化， 青光眼和眼压升高，星形胶质细胞对微环境硬度和眼压高度敏感 机械刺激。虽然广泛使用的小鼠模型成本高昂、耗时且设施有限，但大多数 传统的体外 ONH 模型基于二维刚性基底，没有结合关键的解剖学和 天然 ONH 的生理特征，导致细胞过程偏离体内事件。我们 因此假设 ONH 模型非常类似于物理和机械特性 天然 ONH 将允许更准确的体外青光眼研究。因此，该项目的目标是 开发 ONH 芯片系统，概括关键结构（星形胶质细胞和 RGC 的共培养）， 天然 ONH 的物理（径向对齐 RGC 和基质刚度）和机械 (IOP) 特性 描述青光眼发病机制的星形细胞机制。一个跨学科研究团队已 汇集了芯片器官技术、青光眼神经变性、生物力学和 生物材料，并提出了两个具体目标：（1）设计和验证病理生理学的 ONH 芯片 相关性，（2）在芯片上描绘青光眼发病机制的机械传感机制。 该项目的成功完成将提供新颖的仿生 ONH 芯片，以提供可靠、快速和 描绘青光眼神经变性的廉价模型。经过验证的鼠标 ONH 芯片将被放置 为开发人类 ONH 芯片以推进对青光眼机制的理解奠定基础 发病机制并促进疾病缓解治疗方法的发展。该部门 UNT 生物医学工程学院拥有新近获得 ABET 认证的本科课程，约有 254 名学生 2020 年学生人数（117 名女性，西班牙裔 = 77 名，非洲裔美国人 = 33 名）。拟议的 AREA 计划将 为本科生，特别是代表性不足的少数族裔和女性学生提供研究机会 学生并激励他们在生物医学和健康相关领域追求未来的职业生涯。