HYDROGEN SULFIDE-RELEASING COMPOUNDS AND IOP REGULATION

释放硫化氢的化合物和眼压调节

• 批准号: 8232364
• 负责人: Ya Fatou Njie Mbye
• 金额: $ 41.86万
• 依托单位: TEXAS SOUTHERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232364
• 关键词: ATP sensitive potassium channel complex; Acids; Address; Adverse effects; Aminooxyacetic Acid; Anabolism; Anesthesia procedures; Anterior; Anterior eyeball segment structure; Aqueous Humor; Atrophic; Biological; Biological Preservation; Blindness; Cardiovascular system; Cell Survival; Characteristics; Conscious; Cyclic AMP; Cystathionine; Cysteine; Data; Development; Disease; Enzyme Activators; Enzymes; Eye; Eye diseases; Family suidae; Gases; Glaucoma; Glutamates; Goals; Hydrogen Sulfide; Inflammation; Latanoprost; Lyase; Measures; Mediating; Mediator of activation protein; Methionine; Modeling; Nervous system structure; Neuromodulator; Odors; Optic Nerve; Optics; Organ Culture Techniques; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiological; Play; Process; Production; Regulation; Reporting; Retina; Retinal; Retinal Degeneration; Retinal Detachment; Risk Factors; Role; Signal Transduction; Signaling Molecule; Site; Smell Perception; Smooth Muscle; Sodium; Techniques; Testing; Therapeutic Agents; Therapeutic Uses; Tissues; Topical application; Uvea; Vision; Water; antiglaucoma drug; aqueous; base; design; effective therapy; egg; inhibitor/antagonist; interest; neuroprotection; neuroregulation; neurotransmission; normotensive; novel; novel therapeutics; optic nerve disorder; pollutant; research study; therapeutic target

DESCRIPTION (provided by applicant): Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma, a sight- threatening optic neuropathy that is one of the leading causes of irreversible blindness worldwide. Although current therapies target reduction in IOP, a clinically effective treatment that eradicates progression of visual loss to blindness remains elusive, prompting intense search for potential therapeutic targets. Evidence of the presence of a functional trans-sulfuration pathway in mammalian tissues has stimulated a surge of interest in the biological significance and role of hydrogen sulfide (H2S), a colorless gas with pungent odor of rotten eggs in ocular tissues. To the best of our knowledge, there are few studies that have examined the physiological and/ pharmacological role of H2S (using H2S-releasing compounds) in ocular tissues especially those involved in the regulation of IOP. In this proposed study, we hypothesize that H2S-releasing compounds can regulate IOP and aqueous humor dynamics by an effect that is mediated via conventional and/ uveoscleral pathways. Three specific aims are designed to test the above hypothesis. Specific Aim 1: To determine the effect of H2S- releasing compounds on IOP and aqueous humor dynamics in normotensive rabbits. Specific Aim 2: To investigate the effect and role of H2S-releasing compounds on aqueous humor outflow facility via the conventional and uveoscleral pathway. Specific Aim 3: To determine the mechanism of action of H2S-releasing compounds in regulating aqueous humor outflow. We anticipate that results from the proposed study will demonstrate a physiological/pharmacological role of H2S in the anterior segment of the eye, and also justify the potential use of H2S-based compounds in the development of better and new therapeutic agents for lowering IOP. Furthermore, we expect that findings from this project will be applicable to other ocular diseases, thus opening up new opportunities for the use of H2S-releasing compounds in the preservation of vision. PUBLIC HEALTH RELEVANCE: Due to the fact the current glaucoma therapies do not eradicate loss of vision and replete with side effects, the need to identify additional groups of compounds with specific and potent action on this disease need not be overemphasized. This proposal aims to study the physiological/pharmacological role and mechanism of action of H2S-releasing compounds on ocular tissues of the eye, especially those involved in the regulation of IOP. These studies should provide a better understanding of the role of H2S in diseases of the eye such as glaucoma and aid in identifying better and new classes of IOP-lowering agents with minimal or no adverse effects.

描述（由申请人提供）：眼内压（IOP）升高是青光眼视神经损伤的主要危险因素，青光眼是一种威胁视力的视神经病变，是全世界不可逆性失明的主要原因之一。尽管目前的治疗方法以降低眼压为目标，但临床上有效的治疗方法仍难以消除视力丧失直至失明的进展，这促使人们大力寻找潜在的治疗靶点。哺乳动物组织中存在功能性反式硫化途径的证据激起了人们对硫化氢 (H2S) 的生物学意义和作用的兴趣。硫化氢是一种无色气体，在眼组织中具有臭鸡蛋的刺鼻气味。据我们所知，很少有研究检查 H2S（使用 H2S 释放化合物）在眼组织中的生理和/药理学作用，特别是那些涉及 IOP 调节的组织。在这项拟议的研究中，我们假设释放 H2S 的化合物可以通过传统和/葡萄膜巩膜途径介导的作用来调节眼压和房水动力学。设计了三个具体目标来检验上述假设。具体目标 1：确定释放 H2S 的化合物对血压正常的兔子眼压和房水动力学的影响。具体目标 2：研究释放 H2S 的化合物对房水通过传统途径和葡萄膜巩膜途径流出设施的影响和作用。具体目标 3：确定释放 H2S 的化合物在调节房水流出方面的作用机制。我们预计，拟议研究的结果将证明 H2S 在眼前节中的生理/药理学作用，并证明基于 H2S 的化合物在开发更好的新型降低 IOP 的治疗剂中的潜在用途。此外，我们预计该项目的研究结果将适用于其他眼部疾病，从而为使用释放 H2S 的化合物保护视力开辟新的机会。 公众健康相关性：由于目前的青光眼疗法不能根除视力丧失并且充满副作用，因此无需过分强调识别对这种疾病具有特异性和有效作用的其他化合物组的必要性。本提案旨在研究释放 H2S 的化合物对眼睛组织的生理/药理学作用和作用机制，特别是那些参与 IOP 调节的组织。这些研究应该可以更好地了解硫化氢在青光眼等眼部疾病中的作用，并有助于识别更好的新型降眼压药物，且副作用最小或没有副作用。

项目成果

Pharmacological Actions of Hydrogen Sulfide Donors on Sympathetic Neurotransmission in the Bovine Anterior Uvea, In Vitro.

体外硫化氢供体对牛前葡萄膜交感神经传递的药理作用。

• 发表时间: 2016-05
• 影响因子: 4.4
• 作者: Salvi, Ankita;Bankhele, Pratik;Jamil, Jamal M;Kulkarni;Njie;Ohia, Sunny E;Opere, Catherine A
• 通讯作者: Opere, Catherine A

Interaction between hydrogen sulfide, nitric oxide, and carbon monoxide pathways in the bovine isolated retina.

牛离体视网膜中硫化氢、一氧化氮和一氧化碳途径之间的相互作用。

• 发表时间: 2019
• 影响因子: 2.7
• 作者: Kulkarni;Mitchell;Belford, Remmington;Robinson, Jenaye;Opere, Catherine A;Ohia, Sunny E;Mbye, Ya Fatou N
• 通讯作者: Mbye, Ya Fatou N

Inhibitory action of novel hydrogen sulfide donors on bovine isolated posterior ciliary arteries.

新型硫化氢供体对牛离体睫状后动脉的抑制作用。

• DOI: 10.1016/j.exer.2015.04.001
• 发表时间: 2015-05
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Kulkarni-Chitnis, Madhura;Njie-Mbye, Ya Fatou;Mitchell, Leah;Robinson, Jenaye;Whiteman, Matthew;Wood, Mark E.;Opere, Catherine A.;Ohia, Sunny E.
• 通讯作者: Ohia, Sunny E.