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: 10394920
• 负责人: Reza Dana
• 金额: $ 23.89万
• 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/10394920
• 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（Corneal endothelial cells，CEnC）是维持角膜透明性的关键。许多因素，包括 衰老、氧化应激和炎症与CEnC损伤有关。CEnC损失是一个整体， 许多病理的重要贡献者：它使眼库复杂化，其中长时间的储存导致 CEnC密度的进行性下降，是各种眼部手术后角膜水肿的近端原因。 手术，包括复杂或长期的白内障摘除术、玻璃体切除术或青光眼手术。CEnC损失 也是移植失败的主要近因，无论是否由免疫驱动。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， 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，神经密度和CEnC数量之间存在很强的相关性;许多 包括糖尿病、干眼症和疱疹性角膜炎在内的诱发神经损伤的疾病也与此相关。 可测量的CEnC损失。我们的初步体外和离体数据显示：（1）高组成型表达的 人和哺乳动物中神经肽α-黑素细胞刺激激素（α-MSH）的黑皮质素受体 小鼠CEnC，（2）显著抑制由炎性细胞因子或氧化剂诱导的CEnC死亡 过氧化氢（α-MSH）。和3）当供体组织保存在眼库中时， 培养基中添加α-MSH。基于这些初步数据，我们假设α-MSH提供了 治疗保护CEnC对急性和慢性应激源的反应， 角膜内皮病变具体而言，我们将探索α-MSH在维持CEnC活力中的作用， 急性内皮损伤（Aim 1）和Fuchs样慢性内皮变性（Aim 2）。我们提出的目标是基于我们广泛的初步数据，这些数据显示了α- 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- 在小鼠和人中诱导CEnC凋亡。我们的总体假设是，神经肽α-MSH保护 并响应损伤和退化而再生CEnC。在目的1中，我们检验了α-MSH 通过减少CEnC细胞凋亡和改善CEnC细胞凋亡促进急性角膜损伤后的CEnC再生 在目的2中，我们假设α-MSH可以预防Fuchs样慢性炎症的发病机制。 内皮细胞变性，我们将确定的治疗潜力， 延迟α-MSH治疗保护CEnC和停止/减缓疾病进展。这份补助金 我们的实验室在移植和角膜移植方面拥有广泛的专业知识， 病理生物学，与一个调查小组，其中包括专家对慢性CENC疾病，如福克斯 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 角膜内皮病变治疗的创新。