Damage to Rod Circuitry Underlies Ganglion Cell Functional Changes in Glaucoma

青光眼中神经节细胞功能变化的基础是杆状电路的损伤

• 批准号: 8978412
• 负责人: JASDEEP SABHARWAL
• 金额: $ 4.81万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-31 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978412
• 关键词: Blindness; Brain; Cell Death; Cell physiology; Cells; Cessation of life; Clinic; Clinical; Cone; Custom; Dependence; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Marker; Disease Progression; Early Diagnosis; Early identification; Experimental Models; Eye; Functional disorder; Glaucoma; Goals; Investigation; Knowledge; Left; Light; Maps; Measures; Mediating; Modeling; Modification; Mus; Noise; Ocular Physiology; Output; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiologic Intraocular Pressure; Physiology; Procedures; Property; Protocols documentation; Quality of life; Recovery of Function; Relative (related person); Reporting; Retina; Retinal; Retinal Ganglion Cells; Risk; Risk Factors; Role; Shapes; Side; Staging; Stimulus; Testing; Time; TimeLine; Translating; Vertebrate Photoreceptors; Vision; Visual; Work; arm; base; design; effective intervention; fluid flow; ganglion cell; improved; mouse model; multi-electrode arrays; novel diagnostics; public health relevance; receptive field; response; retinal rods; spatiotemporal; tool

 DESCRIPTION (provided by applicant): Glaucoma is the second leading cause of blindness worldwide and current forms of treatment only halt disease progress. For this reason, identifying and treating glaucoma patients prior to significant visual damage represents the best way to improve patient quality of life. Increased intraocular pressure (IOP) is the biggest risk factor fo glaucoma and focus of current treatment. A recently developed experimental model of glaucoma in the mouse raises IOP by injecting beads into the eye to block fluid flow. The bulk of glaucoma studies have focused on retinal ganglion cell (RGC) death, but recent investigation in this experimental model found that functional deficits in RGCs are observable prior to cell death. RGC function is derived from the convergence of unique upstream circuitry, which can broadly be broken down into rod dominated circuitry for encoding dim light and cone dominated circuitry for encoding bright light. The rod pathway can be further broken down into specific pathways. Loss of night and peripheral vision along with selective death of large RGCs early in glaucoma pathogenesis indicates dysfunction in the rod dominated circuitry. No study has been carried out to directly determine if these circuits are more susceptible to glaucomatous damage. In order to answer this question a multielectrode array (MEA) will be used to record activity from many RGCs while IOP is modulated. Using subsequent analysis procedures RGC functional properties can be extracted from RGC activity. Pairing the IOP-induced damage with circuit isolation allows determination of the dependence of IOP-induced damage on rod and cone pathways. Experimentally two strategies can be used to isolate specific circuitry contribution to RGC properties. The first approach can broadly isolate the rod and cone circuitry by using dim and bright light, respectively. The second approach uses Bhlhb4(-/-) mice which have disrupted rod bipolar cells causing deficiency in the most sensitive rod pathway, the primary pathway. Using these approaches we will determine if glaucoma, via elevated IOP, depends on the rod circuits or subcircuits to alter RGC properties. The findings from this study can be directly translated into novel diagnostic tests for earlier disease detection.

 描述（由适用提供）：青光眼是全球失明和当前治疗形式仅停止疾病进展的第二大主要原因。因此，在明显的视觉损害之前识别和治疗青光眼患者是改善患者生活质量的最佳方法。眼内压力（IOP）是最大的危险因素FO青光眼和当前治疗的重点。最近开发的小鼠青光眼实验模型通过将珠子注入眼睛以阻断流体流量，从而提高了IOP。大部分青光眼研究集中在视网膜神经节细胞（RGC）死亡上，但是在该实验模型中最近的研究发现，在细胞死亡之前，RGC中的功能缺陷是可观察到的。 RGC函数源自唯一上游电路的收敛，可以将其大致分解为杆主导的电路，以编码昏暗的光线和锥体主导的电路，以编码明亮的光。杆途径可以进一步分解为特定的途径。在青光眼发病机理早期，夜间和周围视力的丧失以及大型RGC的选择性死亡表明，杆以电路为主的功能障碍。尚未进行研究以直接确定这些电路是否更容易受到青光眼损伤的影响。为了回答这个问题，在调制IOP时，将使用多电极阵列（MEA）记录许多RGC的活动。使用随后的分析程序RGC功能属性可以从RGC活性中提取。将IOP诱导的损伤与电路隔离配对，可以确定IOP诱导的损伤对杆和锥形途径的依赖性。实验性的两种策略可用于隔离对RGC特性的特定电路贡献。第一种方法可以分别使用昏暗的光线和明亮的光扩展棒和锥电路。第二种方法使用BHLHB4（ - / - ）小鼠，这些小鼠破坏了杆双极细胞，导致最敏感的杆途径（主要途径）缺乏。使用这些方法，我们将通过升高的IOP确定青光眼是否取决于杆电路或亚电路以改变RGC特性。这项研究的发现可以直接转化为用于早期疾病检测的新型诊断测试。