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)是维持角膜透明度的关键。许多因素，包括 衰老、氧化应激和炎症已被认为与CENC损伤有关。CENC损失是一个整体， 许多病理的重要因素：它使眼部银行变得复杂，长期储存会导致 CENC密度进行性下降，是各种眼球术后角膜水肿的近端原因 手术包括复杂或延长的白内障摘除、玻璃体切除或青光眼手术。CENC损失 也是移植物失败的主要直接原因，无论是否由免疫驱动。因此，细胞保护策略 这增强了CENC的生存能力，可能会对许多本来会产生重大影响的环境产生重大影响 导致CENC失代偿和角膜水肿。来自多个临床和实验的临床数据 研究表明，神经密度和CENC数量之间有很强的相关性； 糖尿病、干眼症和疱疹病毒性角膜炎等引起神经损伤的疾病也与此有关。 具有可测量的CENC损失。我们的初步体外和体外数据显示：(1)高结构性表达 人和人神经肽α-MSH的黑素皮质素受体 小鼠CENC，(2)显著抑制炎症细胞因子或氧化剂诱导的CENC死亡 过氧化氢的α-MSH分析。3)保存供体组织后，眼库CENC损失减少 培养基中添加α-MSH。根据这些初步数据，我们假设α-MSH提供了 CENC对急性和慢性应激源的治疗保护 角膜内皮病。具体地说，我们将探索α-MSH在维持CENC生存中的作用， 急性内皮损伤(AIM 1)和Fuchs样慢性内皮变性(AIM)的完整性和功能 2)。我们提出的目标基于我们广泛的初步数据，这些数据显示了α的再生效应- MSH对小鼠CENC创面愈合的影响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CENC细胞凋亡。我们的主要假设是神经肽α-msh可以保护 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 减少CENC凋亡和改善CENC促进急性角膜损伤后CENC再生 增殖和迁移；在目标2中，我们假设α-MSH预防Fuchs样慢性疾病的发病 通过减少氧化应激引起的内皮退行性变，我们将确定 延迟α-MSH治疗在保护慢性鼻咽癌和阻止/减缓疾病进展方面的作用。这笔赠款带来了 我们的实验室在移植和角膜方面拥有广泛的专业知识 病理生物学，一个调查小组，其中包括慢性CENC疾病专家，如Fuchs 营养不良(尤尔库纳斯博士)和神经肽生物学(泰勒博士)。来自该项目的数据很可能导致 角膜内皮病理治疗的创新。