Hypothalamic Control of IOP, ICP, and the Translaminar Pressure Gradient

青光眼是世界范围内致盲的主要原因之一，但我们仍在努力对导致视网膜神经节细胞死亡的机制有一个基本的了解。眼压（IOP）波动最近被确定为青光眼进展的危险因素。有充分的证据表明，人类和啮齿动物的IOP在24小时内以周期性的方式变化，压力峰值出现在早晨醒来时。此外，在青光眼患者中，颅内压（ICP）下降，并假定在筛板上的层间压梯度增加。PI最近发现，在大鼠模型中，用二环碱（BMI; 30pmol/75nl）对下丘脑背内侧和皮层周围神经元进行化学刺激可引起IOP、ICP和层间压力梯度的显著增加。由于DMH/PeF神经元接受视交叉上核的直接和间接投射，他的实验室假设DMH/PeF神经元可能是IOP昼夜波动和层间压力梯度控制的关键效应途径。PI是一位接受过奖学金培训的青光眼专家和神经生物学研究生培训的临床科学家。在这种机制下，PI提出了一个指导临床科学家的研究职业发展计划，该计划将为他提供额外的培训，以帮助表征该模型并识别与IOP和ICP变化有关的潜在神经递质。具体目标#1将包括对房水生成的荧光光度分析和DMH/PeF神经元化学刺激后立即流出设施的体内记录的培训。具体目标#2将专注于将青光眼动物模型纳入他目前的研究，并学习关键的分子生物学技术，这些技术将有助于识别DMH/PeF区域化学刺激后下丘脑介导的IOP和ICP增加所涉及的潜在神经递质。本研究结果将促进我们对神经生理学介导眼压波动和层间压梯度变化的理解。我们预计，进一步确定这一途径和所涉及的神经递质将为旨在降低IOP波动的新型青光眼治疗提供靶点。

DESCRIPTION (provided by applicant): Glaucoma is one of the leading causes of blindness worldwide, yet we are still trying to develop a fundamental understanding of the mechanisms that cause retinal ganglion cell death. Intraocular pressure (IOP) fluctuation has recently been identified as a risk factor for glaucoma progression. There is ample evidence demonstrating that IOP varies in a cyclical manner over a 24-hour period in both human and rodents, with the peak pressure occurring in the morning hours upon awakening. Further, decreases in intracranial pressure (ICP), with postulated increases in the translaminar pressure gradient across the lamina cribrosa, has been reported in glaucoma patients. The PI recently identified that chemical stimulation of dorsomedial and perifornical hypothalamic neurons with bicuculline methoidide (BMI; 30pmol/75nl) evokes substantial increases in IOP, ICP, and the translaminar pressure gradient in the rat model. Because DMH/PeF neurons receive direct and indirect projections from the suprachiasmatic nucleus, his laboratory has hypothesized that the DMH/PeF neurons may be a key effector pathway for circadian fluctuation of IOP and control of the translaminar pressure gradient. The PI is a fellowship trained glaucoma specialist and clinician-scientist with graduate training in neurobiology. Under this mechanism, the PI proposes a mentored clinical-scientist research career development program that will provide him with additional training to help characterize this model and identify potential neurotransmitters involved in the IOP and ICP changes. Specific Aim #1 will include training in fluorophotometric analysis of aqueous humor production and in vivo recording of outflow facility immediately following chemical stimulation of the DMH/PeF neurons. Specific Aim #2 will focus on the incorporation of animal models of glaucoma into his current research and learning key molecular biology techniques that will help identify potential neurotransmitters involved in hypothalamically mediated increases in IOP and ICP following chemical stimulation of the DMH/PeF region. The results of this research will advance our understanding of the neurophysiology mediating fluctuations in IOP and shifts in the translaminar pressure gradient. We anticipate that further defining this pathway and the neurotransmitters involved will provide targets for novel glaucoma therapies aimed at reducing IOP fluctuations.