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: 8212109
• 负责人: CLAIRE H MITCHELL
• 金额: $ 51.99万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212109
• 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; 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; intravitreal injection; 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）：青光眼是世界上失明的主要原因，其特征是视网膜神经节细胞的丧失。尽管该疾病与眼内压（IOP）密切相关，但尚不清楚这种压力如何导致细胞死亡。该建议基于以下新假设，该假设升高IOP会触发ATP的释放，ATP过度刺激了视网膜神经节细胞上的细胞毒性P2X7受体。使用青光眼的大鼠模型将证实依赖压力依赖性ATP的证据，而P2X7受体刺激的毒性作用将在体内确定。两种方法激活的凋亡前基因将被表征并进行比较，以确定对体内压力压力反应的嘌呤能成分。 ATP和P2X7受体刺激释放的机制将在细胞水平上进行探测。将确定Pannexin Hemichannels在ATP释放中的作用，该ATP伴随神经节细胞拉伸和肿胀的作用将得到确定，并且将通过记录细胞内钙水平和整个细胞离子离子电流来评估该释放的ATP自自动刺激P2X7受体在神经节细胞上的能力。将过量ATP的体内证据与负责任机制的识别相结合，确保该提案将具有创新性和相关性，从而提供了新的见解，以了解增加压力损害神经节细胞中青光眼中的神经节细胞。 公共卫生相关性：该项目基于以下假设：视网膜神经节细胞在青光眼中通过压力依赖性ATP释放到视网膜中损害了青光眼，该视网膜神经节细胞上的P2X7受体刺激了P2X7受体。该建议将确认这种关系并探讨如何发生病理释放，以防止青光眼损害的初始阶段。