Purines and the Health of Retinal Ganglion Cells

嘌呤与视网膜神经节细胞的健康

• 批准号: 7781797
• 负责人: CLAIRE H MITCHELL
• 金额: $ 52.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781797
• 关键词: Animal Model; Apoptotic; Blindness; Calcium; Cell Death; Cell Separation; Cell physiology; Cells; Data; Disease; Ensure; Extracellular Space; Figs - dietary; Functional disorder; Funding; Genes; Glaucoma; Grant; Health; Image; In Vitro; Injection of therapeutic agent; Injury; Investigation; Ions; Link; Location; Mechanical Stimulation; Mechanics; Modeling; Participant; Pathway interactions; Physiologic Intraocular Pressure; Physiological; Purines; Rattus; Receptor Activation; Retina; Retinal; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Staging; Stretching; Swelling; Techniques; Tissues; Toxic effect; Vision; age effect; base; cell injury; cytotoxic; experience; extracellular; ganglion cell; in vivo; in vivo Model; injured; innovation; insight; killings; neurotoxic; novel; patch clamp; pressure; prevent; public health relevance; purine; receptor; research study; response

DESCRIPTION (provided by applicant): Glaucoma is a major cause of blindness in the world and is characterized by a loss of retinal ganglion cells. Although the disease is closely associated with elevated intraocular pressure (IOP), it is unclear how this pressure leads to cell death. This proposal is based upon the novel hypothesis that elevated IOP triggers the release of ATP which over-stimulates cytotoxic P2X7 receptors on retinal ganglion cells. Evidence for pressure-dependent ATP release will be confirmed using rat models of glaucoma, while the toxic effects of P2X7 receptor stimulation will be determined in vivo. The pre-apoptotic genes activated by both approaches will be characterized and compared to identify the purinergic component of the response to pressure in vivo. The mechanisms underlying the release of ATP and of P2X7 receptor stimulation will be probed on a cellular level. The role of pannexin hemichannels in the ATP release that accompanies ganglion cell stretch and swelling will be determined, and the ability of this released ATP to autostimulate P2X7 receptors on ganglion cells will be evaluated by recording intracellular calcium levels and whole cell ion currents. Combining in vivo evidence for excess ATP with the identification of the responsible mechanisms ensures this proposal will be both innovative and relevant, providing new insight into how increased pressure damages ganglion cells in glaucoma. PUBLIC HEALTH RELEVANCE: This project is based on the hypothesis that retinal ganglion cells are damaged in glaucoma by pressure-dependent release of excess ATP into the retina which stimulates P2X7 receptors on retinal ganglion cells. This proposal will confirm this relationship and explore how this pathological release occurs with the aim of preventing the initial stages of damage in glaucoma.

描述（由申请人提供）：青光眼是世界上导致失明的主要原因，其特征是视网膜神经节细胞损失。尽管该疾病与眼内压（IOP）升高密切相关，但尚不清楚这种压力如何导致细胞死亡。该提议基于新的假设，即升高的 IOP 会触发 ATP 的释放，从而过度刺激视网膜神经节细胞上的细胞毒性 P2X7 受体。压力依赖性 ATP 释放的证据将通过青光眼大鼠模型得到证实，同时 P2X7 受体刺激的毒性作用将在体内确定。对两种方法激活的预凋亡基因进行表征和比较，以确定体内压力反应的嘌呤能成分。 ATP 释放和 P2X7 受体刺激的潜在机制将在细胞水平上进行探讨。将确定pannexin半通道在伴随神经节细胞拉伸和肿胀的ATP释放中的作用，并且将通过记录细胞内钙水平和全细胞离子电流来评估所释放的ATP自动刺激神经节细胞上的P2X7受体的能力。将过量 ATP 的体内证据与责任机制的识别相结合，确保该提议既具有创新性又具有相关性，为了解压力增加如何损害青光眼中的神经节细胞提供了新的见解。 公共健康相关性：该项目基于以下假设：青光眼中视网膜神经节细胞因压力依赖性释放过量 ATP 进入视网膜而受损，从而刺激视网膜神经节细胞上的 P2X7 受体。该提案将证实这种关系，并探讨这种病理释放是如何发生的，目的是预防青光眼早期阶段的损害。