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.

虽然青光眼的发生率不断增加，但不可逆的主要原因 全世界的失明，当前的青光眼疗法显示出有限的功效。作为最突出的因果关系 青光眼，眼内压（IOP）的预后危险因素可能会变形视神经头 （ONH）并在视网膜神经节细胞（RGC）穿过ONH时损坏它们。当前的青光眼 疗法专注于降低IOP，但是尽管IOP控制了良好，但随着时间的流逝，视力丧失仍在继续。 大量证据表明，ONH星形胶质细胞对升高IOP的响应是RGC轴突的机制 损害。星形胶质细胞表达机械敏感的通道，感知机械变形并变为 响应IOP升高的反应性，这可能导致青光眼的病理变化。但是， IOP对ONH生物力学的影响尚不完全了解。值得注意的是，ONH刚度随着年龄的增长而变化， 青光眼和IOP升高，星形胶质细胞对微环境刚度高度敏感 机械刺激。虽然使用广泛的鼠标模型成本高昂，耗时和设施有限，但大多数 常规的体外ONH模型基于2-D刚性底物，而无需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，假设与与物理和机械特征相似的ONH模型 天然ONH将允许更准确的体外青光眼研究。因此，该项目的目的是 开发片芯片系统，这些系统概括了关键结构（星形胶质细胞和RGC的共培养）， 物理（径向对齐的RGC和基质刚度），以及天然ONH的机械特征（IOP）特征 描述青光眼发病机理的星形细胞机制。一个跨学科研究团队已经 组装成具有器官片技术，青光眼神经变性，生物力学和的专业知识 提出了生物材料和两个具体目的：（1）工程师和验证病理生理学的ONH芯片 相关性和（2）芯片上青光眼发病机理的划定机械传感机制。 该项目的成功完成将提供新颖的仿生芯片，以提供可靠，快速且 较便宜的模型来描述青光眼神经退行性。经过验证的鼠标芯片将放置 开发人类芯片以提高青光眼的机械理解的基础 发病机理并促进疾病改良治疗方法的发展。部门 UNT的生物医学工程有一个新的教abet学科的本科课程，约有254个 学生（117名女性，西班牙裔= 77，非裔美国人= 33）在2020年。拟议的地区计划将 为本科生提供研究机会，特别是对于代表性不足的少数群体和女性 学生并激励他们从事与生物医学和健康相关领域的未来职业。