Mesenchymal stromal cells for treatment of radiation-induced xerostomia

间充质基质细胞用于治疗辐射引起的口干症

• 批准号: 10649465
• 负责人: Cristina Paz
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649465
• 关键词: Acute; Address; Adipose tissue; Adverse effects; Affect; Anatomy; Architecture; Bone Marrow; Cell Therapy; Cell physiology; Cells; Chronic; Clinical; Clinical Research; Cryopreservation; Data; Development; Esthesia; Functional disorder; Future; Goals; Growth and Development function; Head and Neck Cancer; Head and neck structure; In Vitro; Injections; Interferon Type II; Knowledge; Licensing; Long-Term Effects; Marrow; Mentors; Modality; Modeling; Mus; Organ; Organoids; Paracrine Communication; Patients; Perception; Phase; Pilocarpine; Production; Property; Quality of life; Radiation; Radiation exposure; Radiation induced damage; Radiation therapy; Radiosurgery; Regenerative capacity; Reporting; Research Personnel; Role; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Source; Submandibular gland; Therapeutic; Time; Tissues; Translating; Work; Xerostomia; cancer type; career development; design; educational atmosphere; effective therapy; epithelial stem cell; exosome; first-in-human; functional improvement; head and neck cancer patient; healing; immunoregulation; improved; in vivo; ineffective therapies; insight; mesenchymal stromal cell; morphogens; mouse model; novel therapeutics; palliation; palliative; paracrine; phase 1 study; prevent; radiation delivery; radiation effect; side effect; stem cell biology; therapeutic development; training opportunity; treatment optimization

PROJECT SUMMARY/ABSTRACT Radiation-induced xerostomia (RIX) is a condition of subjective dry mouth caused by radiation therapy to the head and neck and manifested as hyposalivation and altered sialochemistry. RIX is the most common chronic side effect observed in HNC patients receiving radiation therapy and despite improvements in radiation delivery remains a critical issue for patients. Currently available treatments provide temporary palliation and in some cases (e.g. pilocarpine) can be accompanied by side effects that are as bad or worse than xerostomia. There is a critical need for a treatment that will safely and effectively alleviate RIX without compromising patient quality of life. A small phase I study suggested that MSC therapy could improve the perception of dry mouth and salivary gland function in patients with RIX. However, the mechanisms by which MSCs elicit this effect remain unknown and none of the successful studies investigated to use of cryopreserved MSCs. We aim to fill this important knowledge gap by identifying an optimal source of MSCs for treatment and understanding how MSCs improve salivary function to optimize treatment to maximize patient benefit. This proposal intends to fill this knowledge gap which will potentially lead to the development of novel and effective therapies for RIX. We hypothesize that MSCs provide a reparative effect to the salivary gland through paracrine signaling. We will investigate the short-term and long-term functions of MSCs following injection into the submandibular gland and identify whether there is an ideal potential tissue source for MSCs in terms of cryo-recovery and RIX treatment. We seek to address three questions critical to understand and treat RIX: 1) identify an ideal tissue source for MSC to treat RIX; 2) investigate the effects of MSC treatment on the salivary gland in acute and late-phase radiation damage; and 3) determine if MSC-based products elicit the same effects as MSCs alone. In Aim 1, we will evaluate the ability of MSCs derived from marrow, adipose, and submandibular gland tissue to recover after cryopreservation following IFN-ɣ pre-licensing and evaluate the effects of these MSCs on salivary tissue in vivo and in vitro. We will characterize the secretome of MSCs from different tissue origins alone and investigate bi-directional effects of salivary gland tissue on this secretome using a salivary organoid model. Finally, we will confirm in vivo, differences in reparative effects based on MSC source. In Aim 2, we will define the effects of IFN-ɣ pre-licensed, cryopreserved MSCs in RIX by studying both acute and long-term effects on saliva production and salivary gland architecture in-vivo. We will also investigate the effects of MSC- based products like MSC conditioned media and MSC-derived exosomes on salivary function in vivo and in vitro. Together this work will provide an improved understanding of how MSCs ameliorate radiation damage, support the development of novel therapeutics for the treatment of RIX, and provide an outstanding training opportunity for the PI.

项目摘要/摘要 辐射引起的静态症（RIX）是由放射治疗引起的主观干口口的疾病 在头颈部，表现为缺失和唾液化学的改变。 rix是最常见的 在接受放射疗法和辐射目的地改善的HNC患者中观察到的慢性副作用 对于患者来说，分娩仍然是一个关键问题。当前可用的治疗可提供临时抚慰和 某些情况（例如，毛果石）可能伴随着比静态症一样严重或更糟的副作用。 对治疗的迫切需要可以安全有效地减轻RIX而不会妥协 病人的生活质量。一项小研究研究表明，MSC治疗可以改善对干燥的看法 RIX患者的口腔和唾液腺功能。但是，MSC引起的机制 效应仍然未知，没有研究的一项成功的研究用于使用冷冻保存的MSC。我们的目标 通过确定最佳的MSC来源来填补这一重要的知识差距，以进行治疗和理解 MSC如何改善唾液功能以优化治疗以最大程度地提高患者益处。该提议打算 填补这一知识差距，这可能会导致RIX的新颖和有效疗法的发展。 我们假设MSC通过旁分泌信号传导为唾液腺提供了修复作用。 我们将调查注入下颌下的MSC的短期和长期功能 腺体并确定在冷冻发现和RIX方面是否有理想的MSC潜在组织来源 治疗。我们试图解决以了解和治疗RIX至关重要的三个问题：1）确定理想的组织 MSC治疗RIX的来源； 2）研究MSC治疗对急性和 后期辐射损伤； 3）确定基于MSC的产品是否会产生与MSC相同的效果。 在AIM 1中，我们将评估源自骨髓，脂肪和下颌下腺组织的MSC的能力 在冷冻保存后恢复后，遵循IFN-ɣ预先许可并评估这些MSC对 体内和体外的唾液组织。我们将表征来自不同组织起源的MSC的分泌组 单独并研究了使用唾液器官 模型。最后，我们将在体内确认基于MSC源的修复效应的差异。在AIM 2中，我们将 通过研究急性和长期来定义RIX中IFN-ɣ预先许可的，冷冻保存的MSC的影响 在体内对唾液生产和唾液腺建筑的影响。我们还将研究MSC-的影响 基于MSC调节培养基和MSC衍生的外泌体等基于唾液功能的体内和中的外泌体 体外。这项工作将共同提高对MSC如何改善辐射损害的理解， 支持开发新疗法以治疗RIX，并提供出色的培训 PI的机会。