Elucidating the Mechanisms of Salivary Gland Dysfunction Following Gamma-Irradiation Utilizing an Experimental and Computational Approach

利用实验和计算方法阐明伽马射线照射后唾液腺功能障碍的机制

基本信息

批准号：
10544347
负责人：
Amanda Michelle Wahl
金额：
$ 4.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544347
关键词：
3-Dimensional Acinar Cell Acute Address Adenosine Triphosphate Ageusia Agonist Bioenergetics Biological Assay Calcium Calcium Signaling Cell Death Cells Characteristics Chlorides Collaborations Communication Computer Models Data Development Diagnosis Duct (organ) structure Ductal Epithelial Cell Experimental Models Fluids and Secretions Functional disorder Gap Junctions Gland Head and Neck Cancer In Vitro Individual Laboratories Lead Liquid substance Microscopy Mitochondria Modeling Mus Pathology Patients Permeability Physiology Process Production Proteins Radiation therapy Role Saliva Salivary Salivary Glands Signal Transduction Structure Submandibular gland Techniques Testing Tight Junctions Tissues United States Xerostomia attenuation calcium uniporter cell type computerized tools design experimental study fluid flow gamma irradiation improved in vivo interest intravital microscopy irradiation loss of function mitochondrial permeability transition pore neglect novel therapeutic intervention oral infection palliative prevent reconstruction saliva secretion side effect standard care therapy development three-dimensional modeling tumor uptake

项目摘要

Individuals diagnosed with head and neck cancer undergo radiation therapy as a standard treatment. However, in the process of using radiation therapy to shrink the tumor, the salivary glands are inadvertently and irreversibly damaged. This damage manifests as a loss of saliva secretion, occurs rapidly without marked cell death, and leads to deleterious effects, including loss of taste, oral infections, and xerostomia (dry mouth). The mechanism by which this early loss of function occurs, is currently unknown and presently there is little in the form of treatment, with most options being palliative. Thus, there is a pressing need to expand our understanding of salivary gland physiology and the effects of γ-irradiation on both the structure and function of the salivary gland. This proposal utilizes experimental techniques including confocal, Stimulated Emission Depletion (STED) and intravital microscopy. Each technique will be employed for use in a variety of assays to investigate the structural and functional consequences of acute γ-irradiation on salivary glands. This in vitro and in vivo experimental approach will additionally be used in combination with computational modeling through a long-term collaboration to understand in detail the effect of γ-irradiation on secretion. In an iterative manner, experimental data will be input to the computation model and subsequently used to make further predictions which will be experimentally tested- furthering our understanding of physiology and pathology of salivary glands. In these studies, this experimental-computational approach will be used to determine how alterations within the salivary gland impact its function, leading to dry mouth, and an eventual permanent loss of glandular tissue and function. This proposal addresses three different mechanisms that may dictate this loss of function. These include an alteration in functioning of gap and tight junctions, calcium signaling, and mitochondrial bioenergetics. By examining each of these aspects, the experimental data can be integrated into the computational model. The great utility of this approach is that many iterations of computational experiments can be completed in parallel with these in vitro and in vivo studies and used to suggest further experiments and make predictions. The dynamic utilization of this computational-experimental approach will facilitate understanding how an alteration in a component of the gland’s secretory machinery following γ-irradiation might alter saliva production. Ultimately, this approach is designed to forecast potential novel therapeutic approaches for treating γ-irradiation induced salivary dysfunction.

被诊断患有头颈癌的个体接受放射治疗作为标准治疗。在利用放射治疗缩小肿瘤的过程中，唾液腺在不经意间发生了不可逆的变化这种损伤表现为唾液分泌丧失，发生迅速，没有明显的细胞死亡，并且导致有害影响，包括味觉丧失、口腔感染和口干症（口干）。这种早期功能丧失是如何发生的，目前尚不清楚，而且目前很少有治疗，大多数选择都是姑息治疗，因此，迫切需要扩大我们对治疗的了解。唾液腺生理学以及γ射线照射对唾液腺结构和功能的影响。该提案利用了实验技术，包括共聚焦、受激发射损耗 (STED) 和每种技术都将用于各种分析中以研究结构。以及急性 γ 辐射对唾液腺的功能影响。体外和体内实验。此外，通过长期合作，该方法还将与计算建模结合使用为了详细了解 γ 辐射对分泌的影响，将以迭代的方式获得实验数据。输入到计算模型，随后用于进行进一步的预测，这些预测将通过实验进行在这些研究中，这进一步加深了我们对唾液腺生理学和病理学的理解。实验计算方法将用于确定唾液腺内的变化如何影响它的功能，导致口干，并最终永久丧失腺体组织和功能。解决了可能导致这种功能丧失的三种不同机制，其中包括功能的改变。通过检查每一项，间隙和紧密连接的功能、钙信号传导和线粒体生物能学。这些方面，实验数据可以整合到计算模型中，这有很大的用处。方法是计算实验的许多迭代可以与这些体外实验并行完成和体内研究并用于建议进一步的实验并做出预测。这种计算实验方法将有助于理解 γ-辐射后腺体的分泌机制可能会改变唾液的产生，这种方法最终是有效的。旨在预测治疗 γ 辐射诱导唾液腺的潜在新治疗方法功能障碍。