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

下丘脑对 IOP、ICP 和层压梯度的控制

基本信息

批准号：
9119119
负责人：
Brian Christopher Samuels
金额：
$ 21.09万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119119
关键词：
Address Adrenal Cortex Hormones Animal Model Animals Aqueous Humor Area Attenuated Behavior Bicuculline Blindness Brain Cell Death Cell Nucleus Chemical Stimulation Circadian Rhythms Clinical Control Locus Data Disease Disease Progression Ensure Eye Fellowship Glaucoma Goals Health Heart Rate Hour Human Hypothalamic structure Intracranial Pressure Laboratories Laboratory Finding Learning Mammals Measurement Mediating Mentors Methods Modeling Molecular Biology Techniques Neuraxis Neurobiology Neurons Neurotransmitters Optic Nerve Pathogenesis Pathway interactions Patients Physiologic Intraocular Pressure Physiological Play Production Proteins RNA Rattus Reporting Research Research Project Grants Retinal Ganglion Cells Risk Factors Rodent Role Scientist Sleep Small Interfering RNA Specialist System Techniques Third ventricle structure Time Training Translating Variant Venous Pressure level Work aqueous humor flow career career development feeding hypocretin in vivo innovation knock-down mind control neurophysiology novel prepro-orexin pressure programs receptor suprachiasmatic nucleus

项目摘要

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.

描述（由申请人提供）：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进行基本了解。眼内压（IOP）波动最近已被确定为青光眼进展的危险因素。有充分的证据表明，在人类和啮齿动物中，IOP在24小时内以周期性方式变化，峰值压力发生在早晨醒来时。此外，在青光眼患者中报告了颅内压（ICP）降低，并假设筛板上的跨板压梯度增加。PI最近发现，在大鼠模型中，用荷包牡丹碱甲苯胺酸（BMI; 30 pmol/75 nl）化学刺激背内侧和穹窿周围下丘脑神经元可引起IOP、ICP和跨板压差显著增加。由于DMH/PeF神经元接受来自视交叉上核的直接和间接投射，因此他的实验室假设DMH/PeF神经元可能是IOP昼夜波动和跨板压梯度控制的关键效应通路。PI是一名接受过研究员培训的青光眼专家和临床医生-科学家，接受过神经生物学研究生培训。在这种机制下，PI提出了一个指导临床科学家研究职业发展计划，将为他提供额外的培训，以帮助描述该模型的特征，并确定IOP和ICP变化中涉及的潜在神经递质。具体目标#1将包括在DMH/PeF神经元的化学刺激后立即进行的房水产生的荧光光度分析和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和学习关键的分子生物学技术，这将有助于确定潜在的神经递质参与下丘脑介导的IOP和ICP增加后，DMH/PeF区域的化学刺激。这项研究的结果将促进我们对神经生理学介导的IOP波动和跨椎板压力梯度变化的理解。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。