Therapeutic vascularization to support repair of damaged salivary glands

治疗性血管化支持受损唾液腺的修复

• 批准号: 10594008
• 负责人: Lisa L Sandell
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594008
• 关键词: Adipose tissue; Angiogenesis Promoter; Autoimmune Diseases; Biological Models; Biology; Biopsy; Blood Vessels; Blood flow; Cell Culture Techniques; Cells; Clinical; Complex; Endothelial Cells; Endothelium; Engineering; Ensure; Epithelium; Event; FDA approved; Fibroblasts; Gene Expression; Genetic Transcription; Gland; Growth; Implant; In Vitro; Individual; Inflammation; Knowledge; Malignant Neoplasms; Methods; Microbubbles; Molecular; Mus; Natural regeneration; Organ; Pathology; Patients; Perfusion; Pericytes; Persons; Pharmaceutical Preparations; Pilot Projects; Pre-Clinical Model; Production; Proliferating; Radiation therapy; Recovery; Retinoids; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Skin; Smooth Muscle Myocytes; Source; Submandibular gland; Supporting Cell; System; Tazarotene; Testing; Therapeutic; Therapeutic Uses; Tissue Engineering; Tissues; Transplantation; Vascular Smooth Muscle; Vascularization; Vitamin A; Wound models; angiogenesis; blood vessel development; cell type; effective therapy; experience; healing; implantation; in vitro Assay; in vivo; knowledge of results; novel; novel therapeutics; pharmacologic; repaired; replacement tissue; small molecule; success; therapeutic angiogenesis; wound; wound healing

Project Summary Damage to salivary glands is a devastating condition – identification of therapies to promote regeneration of these important organs is imperative. Great progress is being made in engineering and transplantation of salivary gland epithelium. A major remaining hurdle in gland engineering is the need to establish a functional vasculature, which is essential for survival of any replacement tissue in vivo. In addition to essential support, therapeutic angiogenesis also stimulates healing of non-vascular tissue. This study will characterize methods of promoting vascularization in regenerating salivary gland tissues. Using mice as a pre-clinical model system, we will evaluate two distinct therapeutic approaches – individually and in combination – to promote vascularization and regeneration of damaged glands. One therapeutic approach involves implantation of an exogenous vascular cell milieu as a method to enhance formation of functional blood vessel networks. The other approach, which may be effective when used in conjunction with implanted cells, or on its own, will involve systemic delivery of a drug with potential to stimulate angiogenesis. The therapeutic potentials of the of the two approaches will be evaluated separately and in combination in vivo in mice in a biopsy wound healing model. Cellular and molecular events of vascular assembly associated with each therapy will be defined using cell culture assays in vitro. For implantation of vascular cells, we will use a cell milieu of stromal vascular fraction derived from adipose (AdSVF). The AdSVF cell milieu has real advantages as a cell source. It includes many cell types needed to form functional blood vessel networks (endothelial, pericytes, vascular smooth muscle, fibroblasts) it reduces inflammation to promote regeneration of parenchymal tissue, it is readily available for self-donation, and, importantly, has proven safe for clinical use. As an adjunct to implanted AdSVF, or as a stand-alone vascularizing therapeutic, we will also test the ability of a systemic pharmacologic agent Tazarotene to stimulate formation of functional vascular networks. Tazarotene is a synthetic retinoid. Its vascular promoting activity is consistent with the action of natural retinoids, including vitamin A and its derivative retinoic acid, which are essential for vascular assembly in vivo. This project will identify methods to promote functional vasculature in regenerating salivary glands. Resulting knowledge can be used to enhance success of therapies aimed at repairing salivary epithelium, thereby advancing the field toward developing effective therapies for patients suffering from salivary gland damage.

项目摘要 唾液腺损伤是一种毁灭性的疾病-确定治疗方法， 促进这些重要器官的再生势在必行。正在取得巨大进展， 涎腺上皮的工程化和移植。一个主要的剩余障碍， 腺体工程是需要建立一个功能性的脉管系统，这是生存所必需的 任何替代组织的能力。除了必要的支持，治疗性血管生成还 刺激非血管组织的愈合。这项研究将描述促进 再生唾液腺组织中的血管化。使用小鼠作为临床前模型系统， 我们将评估两种不同的治疗方法-单独和联合-以 促进受损腺体的血管化和再生。一种治疗方法 包括植入外源性血管细胞环境作为增强血管形成的方法， 功能性血管网络。另一种方法，当用于 与植入的细胞结合或单独使用，将涉及药物的全身递送， 刺激血管生成的潜力。这两种方法的治疗潜力将 在活组织检查伤口愈合模型中，在小鼠体内单独和组合进行评价。 将定义与每种治疗相关的血管组装的细胞和分子事件 使用体外细胞培养测定。对于血管细胞的植入，我们将使用 来源于脂肪的基质血管组分（AdSVF）。AdSVF细胞环境具有真实的 作为细胞来源。它包括形成功能性血管所需的许多细胞类型 网络（内皮细胞，周细胞，血管平滑肌，成纤维细胞），它减少炎症 为了促进实质组织的再生，它很容易用于自我捐献，并且， 重要的是，已证明临床使用安全。作为植入的AdSVF的辅助药物，或作为 独立的血管化治疗，我们还将测试系统药理学的能力， 药物他扎罗汀刺激功能性血管网络的形成。他扎罗汀是一种 合成类维生素A其促血管生成活性与天然的 类维生素A，包括维生素A及其衍生物视黄酸，这是血管所必需的， 体内组装。该项目将确定促进功能性脉管系统的方法， 再生唾液腺由此产生的知识可用于提高治疗的成功率 旨在修复唾液腺上皮，从而推动该领域朝着开发有效的 治疗患有唾液腺损伤的患者。