Novel Treatments for Ocular Surface Diseases

眼表疾病的新疗法

• 批准号: 10795227
• 负责人: Vinay Aakalu
• 金额: $ 38.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10795227
• 关键词: Address; Advanced Development; Affect; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Autophagocytosis; Benzalkonium Chloride; Binding; Binding Proteins; Biological Assay; Cell Culture Techniques; Clinical; Copper; Cornea; Custom; Data; Desiccation; Development; Disease; Disease model; Drug Formulations; Dry Eye Syndromes; Endosomes; Ensure; Environment; Enzymes; Epithelium; Exposure to; Family; Film; Functional disorder; Future; G-Protein-Coupled Receptors; Glaucoma; Histidine; Homeostasis; Human; Humidity; IL8 gene; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Interleukin-6; Lacrimal gland structure; Ligands; Mammalian Cell; Matrix Metalloproteinases; Measures; Mediating; Mediator; Metals; Methods; Modeling; Mucositis; Nickel; Oral; Osmolar Concentration; Outcome; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Physiological; Production; Property; Proteins; Protocols documentation; Publishing; Quality of life; Research; Saliva; Stress; System; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicant exposure; Vision; antimicrobial; antimicrobial peptide; clinically relevant; corneal epithelium; cytokine; design; experience; experimental study; histatin 1; histidine-rich proteins; improved; in vivo; in vivo Model; innovation; lacrimal; migration; mouse model; novel; novel therapeutics; ocular surface; ocular surface disease; ophthalmic drug; palliative; receptor; screening; synthetic peptide; translational model; visual dysfunction; wound healing

PROJECT DESCRIPTION/ABSTRACT Dry eye disease (DED) and other ocular surface diseases (OSD) are common conditions that can reduce visual function and quality of life. Commonly used ophthalmic preservatives can cause a toxic epitheliopathy that results in OSD. The treatment of these diseases is primarily through the use of palliative measures. Great opportunity exists to improve the quality of life of many patients by developing novel treatments. DED and OSD are associated with significant dysfunction of corneal epithelia and inflammatory changes on the ocular surface. Many of these changes are induced by hyperosmolarity, desiccation and inflammatory insults. Histatin is a family of peptides found primarily in saliva and is known to have significant wound healing and anti-infective properties. Little data exist on the mechanisms of action of histatin peptides, though some effects are thought to be mediated through as yet unknown receptors. We have found that these peptides can reduce inflammatory changes associated with exposures of toxic preservatives to the ocular surface and in experimental conditions that mimic DED. We have also found a potential novel ligand-receptor interaction for histatin peptides. Our long term objective is to develop a new class of DED and OSD therapeutics which are non-toxic and anti- inflammatory. Our central hypothesis is that histatin peptides can ameliorate the inflammatory effects of toxic and inflammatory insults to corneal epithelia in vitro and in vivo. We will utilize well vetted models of toxic epitheliopathy, hyperosmolarity and desiccation in order to show the efficacy of histatin peptides in treating OSDs. We will also undertake studies to find receptors for histatin peptide. The proposed research is innovative as it is the first study to investigate the use of histatin peptides in the treatment of DED and OSD. These studies are significant because they will advance the development of new therapeutics through the use of rigorous and well defined methods in clinically relevant translational models of disease and validate a novel receptor-ligand relationship.

项目描述/摘要 干眼症（DED）和其他眼表疾病（OSD）是可降低视觉刺激的常见病症。 功能和生活质量。常用的眼科防腐剂可引起毒性上皮病， 导致OSD。这些疾病的治疗主要是通过使用姑息措施。伟大 存在通过开发新的治疗来改善许多患者的生活质量的机会。DED和OSD 与角膜上皮的显著功能障碍和眼表的炎性变化有关。 这些变化中的许多是由高渗、干燥和炎症损伤引起的。组胺素是一个家族 主要存在于唾液中的肽，已知具有显著的伤口愈合和抗感染特性。 关于组胺素肽的作用机制的数据很少，尽管一些作用被认为是 通过未知的受体介导。我们发现这些肽可以减少炎症反应， 与眼表和实验条件下有毒防腐剂暴露相关的变化 模仿DED我们还发现了一个潜在的新的组胺素肽配体-受体相互作用。我们漫长 长期目标是开发一类新的DED和OSD治疗剂，它们是无毒的， 煽动性我们的中心假设是，组胺素肽可以减轻毒性的炎症反应， 以及在体外和体内对角膜上皮的炎性损伤。我们将使用经过严格审查的有毒模型 上皮病、高渗透压和干燥，以显示组蛋白肽在治疗中的功效 OSDs。我们还将进行研究，寻找组胺素肽的受体。该研究具有创新性 因为这是首次研究组胺素肽在治疗DED和OSD中的用途。这些研究 是重要的，因为它们将通过使用严格的， 在疾病的临床相关转化模型中定义明确的方法，并验证新型受体-配体 关系

项目成果

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity.

• DOI: 10.1021/acs.jmedchem.3c00959
• 发表时间: 2023-08-24
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Dichiara, Maria;Ambrosio, Francesca Alessandra;Lee, Sang Min;Ruiz-Cantero, M. Carmen;Lombino, Jessica;Coricello, Adriana;Costa, Giosue;Shah, Dhara;Costanzo, Giuliana;Pasquinucci, Lorella;Son, Kyung No;Cosentino, Giuseppe;Gonzalez-Cano, Rafael;Marrazzo, Agostino;Aakalu, Vinay Kumar;Cobos, Enrique J.;Alcaro, Stefano;Amata, Emanuele
• 通讯作者: Amata, Emanuele