Therapeutic Function of alpha-Melanocyte Stimulating Hormone (α-MSH) in Acute Injury and Chronic Degeneration of Corneal Endothelium

α-黑色素细胞刺激激素（α-MSH）在角膜内皮急性损伤和慢性变性中的治疗作用

• 批准号: 10191281
• 负责人: Reza Dana
• 金额: $ 29.55万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191281
• 关键词: Acute; Adopted; Aging; Antioxidants; Apoptosis; Aqueous Humor; Biology; Cataract Extraction; Cell Count; Cell Death; Cell Density; Cell Proliferation; Cell Survival; Cells; Chronic; Chronic Disease; Clinical Data; Clinical Research; Complex; Cornea; Corneal Endothelium; Corneal Injury; Corneal edema; DNA Damage; Data; Diabetes Mellitus; Disease; Disease Progression; Early treatment; Endothelial Cells; Endothelium; Eye; Eye Banks; FDA approved; Freezing; Fuchs' Endothelial Dystrophy; Glaucoma; Grant; Herpetic Keratitis; Human; Hydrogen Peroxide; Immune; In Vitro; Infection; Inflammation; Inflammatory; Injury; Keratoplasty; Lead; Measurable; Mediating; Medical; Modeling; Morphology; Mus; Natural regeneration; Nerve; Neural Crest; Neuropeptide Receptor; Neuropeptides; Operative Surgical Procedures; Oxidants; Oxidative Stress; Pathogenesis; Pathology; Procedures; Reactive Oxygen Species; Research; Role; Testing; Therapeutic; Time; Tissue Donors; Transplantation; UVA induced; Vision; Vitrectomy; alpha-Melanocyte stimulating hormone; base; cell injury; cell motility; cell regeneration; clinical development; clinically significant; cytokine; density; experimental study; eye dryness; graft failure; improved; in vivo; innovation; irradiation; melanocortin receptor; migration; monolayer; mouse model; nerve damage; novel; preservation; prevent; receptor binding; regeneration potential; regenerative; response; response to injury; standard of care; stressor; synergism; therapeutic evaluation; wound healing

Corneal endothelial cells (CEnC) are critical for maintaining corneal transparency. Many factors, including aging, oxidative stress, and inflammation have been implicated in CEnC damage. CEnC loss is an integral and important contributor to many pathologies: it complicates eye banking where prolonged storage leads to progressive decline in CEnC density, and is the proximal cause of corneal edema after a variety of ocular surgeries including complex or prolonged cataract extraction, vitrectomy, or glaucoma procedures. CEnC loss is also the chief proximate cause of graft failure, whether immune-driven or not. Thus, cytoprotective strategies that enhance CEnC viability could have a major impact on a wide number of settings that would otherwise lead to CEnC decompensation and corneal edema. Clinical data from a number of clinical and experimental studies have demonstrated a strong correlation between nerve density and CEnC numbers; numerous conditions, including diabetes, dry eye, and herpetic keratitis, which induce nerve damage, are also associated with measurable CEnC loss. Our preliminary in vitro and ex vivo data show (1) high constitutive expression of melanocortin receptor for the neuropeptide alpha-melanocyte stimulating hormone (α-MSH) in both human and murine CEnC, (2) significant suppression of CEnC death induced by inflammatory cytokines or the oxidant hydrogen peroxide by α-MSH. and 3) decrease in eye banked CEnC loss when donor tissues are kept in medium supplemented with α-MSH. Based on these preliminary data, we hypothesize that α-MSH provides therapeutic protection for CEnC in response to both acute and chronic stressors associated with corneal endotheliopathy. Specifically, we will explore the role of α-MSH in maintaining CEnC viability, integrity, and function in acute endothelial injury (Aim 1) and Fuchs-like chronic endothelial degeneration (Aim 2). Our proposed aims are grounded on our extensive preliminary data showing the regenerative effect of α- MSH on murine CEnC wound healing and its cytoprotective effect against cytokines and oxidative stress- induced CEnC apoptosis in mice and human. Our overarching hypothesis is that neuropeptide α-MSH protects and regenerates CEnC in response to injuries and degeneration. In Aim 1 we test the hypothesis that α-MSH promotes CEnC regeneration following acute corneal injury by reducing CEnC apoptosis and improving proliferation and migration; in Aim 2 we hypothesize that α-MSH prevents pathogenesis of Fuchs-like chronic endothelial degeneration by reducing oxidative stress and we will determine the therapeutic potential of delayed α-MSH treatment in protecting CEnC and halting/slowing disease progression. This grant brings together synergy between our lab, which has an extensive expertise in transplantation and corneal pathobiology, with an investigative group that includes experts on chronic CEnC disorders such as Fuchs dystrophy (Dr. Jurkunas) and neuropeptide biology (Dr. Taylor). Data from this project could very well lead to innovations in the therapy of corneal endothelial pathologies.

角膜内皮细胞（CENC）对于维持角膜透明度至关重要。许多因素，包括 衰老，氧化应激和炎症已在CENC损伤中实现。 Cenc损失是不可或缺的 引起许多病理学的重要贡献者：这使眼睛堤防复杂化，长时间的存储会导致 Cenc密度的逐渐下降，是各种眼部后角膜水肿的近端原因 手术包括复杂或长时间的白内障，玻璃体切除术或青光眼手术。 cenc损失 无论是否免疫驱动，也是移植失败的主要原因。那是细胞保护策略 增强Cenc的生存能力可能会对多种环境产生重大影响 导致Cenc代偿失调和角膜水肿。来自许多临床和实验的临床数据 研究表明，神经密度与CENC数量之间存在很强的相关性。很多的 疾病，包括糖尿病，干眼症和疱疹性角膜炎，诱发神经损伤，也是相关的 可衡量的cenc损失。我们的初步体外和离体数据显示（1） 黑色皮质素受体用于人和人类和 鼠Cenc，（2）炎症细胞因子或氧化剂诱导的CENC死亡的明显抑制 α-MSH的过氧化氢。 3）当将捐赠者组织保存在供体组织中时减少了眼睛的结肠损失 补充α-MSH的培养基。基于这些初步数据，我们假设α-MSH提供了 CENC的治疗保护，以应对急性和慢性应激源 角膜内皮病。具体而言，我们将探讨α-MSH在维持CENC生存力中的作用， 完整性和急性内皮损伤（AIM 1）和Fuchs样慢性内皮声明（AIM） 2）。我们提出的目标基于我们广泛的初步数据，显示了α-的再生作用 MSH关于鼠Cenc伤口愈合及其对细胞因子的细胞保护作用及其氧化应激 - 小鼠和人类诱导的cenc凋亡。我们的总体假设是神经肽α-MSH保护 并为响应伤害和变性而再生。在AIM 1中，我们检验了α-MSH的假设 通过减少Cenc凋亡并改善急性角膜损伤后促进Cenc再生 扩散和迁移；在AIM 2中，我们假设α-MSH防止了富奇的发病机理 内皮变性通过减少氧化应激，我们将确定 延迟α-MSH治疗在保护CENC和停止/减慢疾病进展方面。这笔赠款带来了 我们的实验室之间的协同作用，该实验室在移植和角膜方面具有广泛的专业知识 病理生物学，包括一个调查小组，其中包括有关慢性病疾病的专家，例如富赫斯 营养不良（Jurkunas博士）和神经肽生物学（Taylor博士）。这个项目的数据很可能导致 角膜内皮病理治疗中的创新。