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，包括许多因素。 衰老、氧化应激和炎症与 CEnC 损伤密切相关。 许多病理学的重要贡献者：它使眼库变得复杂，长期储存会导致 CEnC密度进行性下降，是各种眼科手术后角膜水肿的近端原因。 手术包括复杂或长时间的白内障摘除术、玻璃体切除术或青光眼手术。 也是移植失败的主要原因，无论是否是免疫驱动的，因此，细胞保护策略。 增强 CEnC 的可行性可能会对许多环境产生重大影响，否则这些环境将 导致CEnC失代偿和角膜水肿的临床数据来自多项临床和实验。 研究表明神经密度和 CEnC 数量之间存在很强的相关性； 糖尿病、干眼症和疱疹性角膜炎等引起神经损伤的疾病也与此相关 我们的初步体外和离体数据显示 (1) 高组成型表达。 人和神经肽α-黑素细胞刺激激素（α-MSH）的黑皮质素受体 小鼠CEnC，(2)显着抑制炎症细胞因子或氧化剂诱导的CEnC死亡 α-MSH 产生的过氧化氢；3) 当供体组织保存在眼库中时，CEnC 损失减少。 补充有 α-MSH 的培养基 基于这些初步数据，我们勇敢地说 α-MSH 提供。 CEnC 应对急性和慢性应激源的治疗保护 具体来说，我们将探讨 α-MSH 在维持 CEnC 活力中的作用， 急性内皮损伤（目标 1）和 Fuchs 样慢性内皮变性（目标 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 对小鼠 CEnC 伤口愈合及其对细胞因子和氧化应激的细胞保护作用 诱导小鼠和人类的 CEnC 凋亡。我们的总体假设是神经肽 α-MSH 具有保护作用。 并再生 CEnC 以应对损伤和退化。在目标 1 中，我们检验了 α-MSH 的假设。 通过减少 CEnC 细胞凋亡和改善急性角膜损伤后的 CEnC 再生 增殖和迁移；在目标 2 中，我们追求 α-MSH 可以预防 Fuchs 样慢性病的发病机制 通过减少氧化应激来抑制内皮变性，我们将确定其治疗潜力 延迟 α-MSH 治疗可保护 CEnC 并阻止/减缓疾病进展。 我们的实验室在移植和角膜方面拥有丰富的专业知识，相互协同 病理生物学，其调查小组包括 Fuchs 等慢性 CEnC 疾病专家 营养不良（Jurkunas 博士）和神经肽生物学（Taylor 博士）该项目的数据很可能导致。 角膜内皮病理治疗的创新。