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

被诊断患有头颈癌的患者将接受放射治疗，作为标准治疗。然而， 在使用放射治疗缩小肿瘤的过程中，唾液腺不经意间不可逆转。 损坏了。这种损害表现为唾液分泌的丧失，迅速发生，没有明显的细胞死亡。 会导致不良影响，包括味觉丧失、口腔感染和口干症(口干)。这一机制 发生这种早期功能丧失的原因目前尚不清楚，目前几乎没有 治疗，大多数选择是姑息治疗。因此，迫切需要扩大我们对 唾液腺生理及γ照射对唾液腺结构和功能的影响。 这一建议利用了实验技术，包括共聚焦、受激发射耗尽(STED)和 活体显微镜。每种技术都将被用于各种分析，以研究结构 以及急性γ辐射对唾液腺的功能后果。这是一种体内外实验 此外，还将通过长期合作将该方法与计算建模结合使用 详细了解γ照射对细胞分泌的影响。以迭代的方式，实验数据将被 输入到计算模型中，并随后用于进行进一步的预测，这些预测将在实验中进行 测试-加深我们对唾液腺的生理学和病理学的了解。在这些研究中，这是 实验-计算方法将被用来确定唾液腺内的变化如何影响 它的功能会导致口干，并最终导致腺体组织和功能的永久性丧失。这项建议 阐述了可能导致这种功能丧失的三种不同机制。这些措施包括改变 缝隙和紧密连接、钙信号和线粒体生物能量学的功能。通过检查每一个 在这些方面，可以将实验数据整合到计算模型中。它的巨大用处在于 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 和活体研究，并用来建议进一步的实验和做出预测。资源的动态利用 这种计算-实验方法将有助于理解组件的变化是如何 γ照射后腺体的分泌机制可能会改变唾液的产生。归根结底，这种方法是 旨在预测治疗γ辐射引起的唾液的潜在新治疗方法 功能障碍。

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.