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

• 批准号: 10228326
• 负责人: Amanda Michelle Wahl
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/10228326
• 关键词: 3-Dimensional; Acinar Cell; Acute; Address; Adenosine Triphosphate; 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; Taste Perception; Techniques; Testing; Tight Junctions; Tissues; United States; Xerostomia; attenuation; base; calcium uniporter; cell type; computerized tools; design; experimental study; fluid flow; gamma irradiation; improved; in vivo; interest; intravital microscopy; 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

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人接受放射治疗作为标准治疗。然而，在这方面， 在使用放射治疗缩小肿瘤的过程中，唾液腺无意中且不可逆地 损坏这种损害表现为唾液分泌的丧失，发生迅速，没有明显的细胞死亡， 导致有害影响，包括味觉丧失、口腔感染和口干症（口干）。机制 这种早期功能丧失是如何发生的，目前尚不清楚，目前几乎没有任何形式的 治疗，大多数选择是姑息治疗。因此，迫切需要扩大我们对 唾液腺生理学及γ射线照射对唾液腺结构和功能的影响。 该提议利用实验技术，包括共焦、受激发射耗尽（STED）和 活体显微镜检查每种技术都将用于各种测定以研究结构 急性γ射线照射对唾液腺功能的影响。这种体外和体内实验 此外，还将通过长期合作，将这种方法与计算建模结合使用 详细了解γ射线照射对分泌的影响。以迭代的方式，实验数据将被 输入到计算模型中，随后用于进行进一步的预测， 测试-促进我们对唾液腺的生理和病理学的理解。在这些研究中， 实验-计算方法将被用来确定唾液腺内的改变如何影响 它的功能，导致口干，并最终永久丧失腺体组织和功能。这项建议 解决了可能导致这种功能丧失的三种不同机制。其中包括一项修改， 间隙和紧密连接的功能，钙信号传导和线粒体生物能量学。通过检查每一个 这些方面，实验数据可以集成到计算模型中。这个的巨大效用 方法是，许多迭代的计算实验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和作出预测。的动态利用 这种计算实验方法将有助于理解如何改变的一个组成部分， γ射线照射后腺体的分泌机制可能会改变唾液的产生。最终，这种方法是 旨在预测治疗γ射线诱导的唾液腺疾病的潜在新治疗方法 功能障碍