Nanofiber Scaffolds for Salivary Gland Regeneration

用于唾液腺再生的纳米纤维支架

基本信息

批准号：
10377504
负责人：
MELINDA LARSEN
金额：
$ 67.15万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377504
关键词：
Address Affect Alpha Cell Anti-Inflammatory Agents Autoimmune Diseases Back Bone Marrow Cells Cessation of life Clinical Connective Tissue Deposition Disease Disease Progression Environment Excision Extracellular Matrix Fibrosis Functional disorder Genetic Markers Gland Head and Neck Cancer Immune response Impairment Inbred NOD Mice Inflammation Inflammatory Injections Injury Knowledge Manipulative Therapies Mediating Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells Methods Modeling Mouse Strains Mus Mutation Myofibroblast Nanofiber Scaffold Natural regeneration Non obese Organ Outcome Patients Pharmacology Phenotype Platelet-Derived Growth Factor alpha Receptor Population Porifera Radiation Resected Salivary Salivary Gland Diseases Salivary Glands Severities Signal Transduction Sjogren&apos s Syndrome Source System Therapeutic Tissues Transplantation Work autoimmune inflammation autoimmune pathogenesis base bone marrow mesenchymal stem cell clinically relevant defined contribution diabetic drug discovery functional restoration healing improved in vivo injured injury and repair insight mouse model nanofiber novel therapeutics regenerative remediation response response to injury restoration scaffold stem cell delivery therapeutic target tissue regeneration wound healing

项目摘要

ABSTRACT Although extracellular matrix (ECM) remodeling is a natural response to injury, excessive ECM deposition, or fibrosis, limits regeneration, is a causative factor in hundreds of diseases, and leads to 40% of all deaths worldwide. Fibrosis occurs in salivary glands (SG) of patients treated with radiation for head and neck cancers and in patients suffering from the autoimmune disease, Sjögren’s Syndrome (SS). Despite the known inhibitory effects of fibrosis on tissue regeneration, and involvement of fibrosis in disease, the mechanisms through which fibrosis develops in the salivary gland and leads to dysfunction have not been explored. The stroma of salivary glands and other organs includes tissue-resident mesenchymal stem cells (MSCs). MSCs have inherent anti-fibrotic and anti-inflammatory functions; however, in disease states tissue- resident MSCs can undergo conversion into myofibroblasts (myo-FBs) and contribute to fibrosis. Therapeutic transplantation of MSCs has been used to treat many inflammatory disorders, with the most common tissue source for therapeutic MSCs being bone marrow (BM). Injection of BM-MSCs into non-obese diabetic (NOD) mice, a commonly used mouse model for SS, showed decreased inflammation and some limited SG functional restoration; however, effects were transient and the mechanisms leading to restored function remain unknown. Therapies that manipulate endogenous or apply exogenous MSCs hold clinical promise for diseases involving fibrosis and salivary hypofunction. Mechanisms through which tissue-resident MSCs and transplanted MSCs become fibrosis-generating myo-FBs in the SG are unknown; however, in many tissues signaling by Gli1 is required. We hypothesize that tissue-resident MSCs that undergo conversion to myo-FBs leading to fibrotic connective tissue exacerbating autoimmune disease and salivary dysfunction. The objective of this proposal is to determine if modulation of tissue-resident MSCs can limit fibrosis, inflammation, and restore gland function in injured and diseased salivary glands. We will address several important clinically relevant questions in this proposal: 1) Does Gli1 signaling contribute to fibrosis in injured/diseased salivary glands? 2) Can tissue- resident myo-FBs revert to a pro-regenerative MSC state and what are the associated genetic changes that demark this conversion? 3) In a murine Sjögren’s Syndrome model, will limiting conversion of tissue-resident MSCs into myo-FBs limit fibrosis, decrease disease progression, and facilitate functional restoration? The outcomes of our proposed study are expected to improve scientific knowledge by revealing cellular mechanisms through which MSCs contribute to fibrosis in SG. These findings will have a positive impact by identifying potential therapeutic targets. In addition, we will optimize scaffold delivery systems for MSCs and anti-fibrotic pharmacologicals for reducing fibrosis and restoring function in hypofunctioning salivary glands and other organs.

抽象的尽管细胞外基质 (ECM) 重塑是对损伤、过度 ECM 沉积或纤维化的自然反应，限制再生，是数百种疾病的致病因素，并导致全球 40% 的死亡。发生在接受头颈癌放射治疗的患者以及患有以下疾病的患者的唾液腺 (SG) 中：自身免疫性疾病，干燥综合症（SS），尽管已知纤维化对组织再生有抑制作用，以及纤维化在疾病中的参与，纤维化在唾液腺中发展并导致的机制尚未探索唾液腺和其他器官的基质包括组织驻留间充质。干细胞（MSC）具有固有的抗纤维化和抗炎功能；然而，在疾病状态下组织- 驻留的 MSC 可以转化为肌成纤维细胞 (myo-FB) 并有助于治疗纤维化。间充质干细胞移植已被用于治疗许多炎症性疾病，最常见的组织来源是治疗性 MSC 是将 BM-MSC 注射到非肥胖糖尿病 (NOD) 小鼠中，这是一种常见的治疗方法。使用 SS 小鼠模型，显示炎症减少和 SG 功能恢复有限；是暂时的，导致功能恢复的机制仍然未知。或应用外源性 MSC 对涉及纤维化和唾液功能减退机制的疾病具有临床前景。组织驻留的 MSC 和移植的 MSC 是通过什么途径成为 SG 中产生纤维化的肌 FB 的，目前尚不清楚；然而，在许多组织中，Gli1 信号传导是必需的，我们寻找的是发生这种情况的组织驻留 MSC。转化为肌FB，导致结缔组织纤维化，加剧自身免疫性疾病和唾液功能障碍。该提案的目的是确定组织驻留 MSC 的调节是否可以限制纤维化、炎症和恢复受损和患病唾液腺的腺体功能我们将讨论几个重要的临床相关问题。该提案中的问题：1) Gli1 信号传导是否会导致受损/患病唾液腺的纤维化？2) 组织可以- 常驻肌 FB 恢复到促再生 MSC 状态，以及标记此状态的相关遗传变化是什么 3) 在小鼠干燥综合征模型中，会限制组织内 MSC 向肌FB 的转化吗？限制纤维化、减少疾病进展并促进功能恢复？我们提出的研究的结果是有望通过揭示间充质干细胞促进纤维化的细胞机制来提高科学知识 SG：这些发现将通过确定潜在的治疗靶点产生积极影响。用于减少纤维化和恢复功能的间充质干细胞和抗纤维化药理学的支架输送系统唾液腺和其他器官功能低下。