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：
10401792
负责人：
Amanda Michelle Wahl
金额：
$ 4.76万
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/10401792
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 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

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.

被诊断为头颈癌的人接受放射治疗作为标准治疗。然而，在使用放射疗法缩小肿瘤的过程中，唾液网格是无意中和不可逆转的损坏的。这种损害表现为失去唾液分泌，迅速发生，没有明显的细胞死亡，并且导致有害影响，包括味觉丧失，口腔感染和静脉症（口干）。机制通过这种早期功能丧失的发生，目前未知，存在几乎没有的形式治疗，大多数选择都是姑息治疗。那是迫切需要扩展我们对唾液腺生理和γ辐射对唾液腺结构和功能的影响。该建议利用实验技术，包括共焦，刺激排放耗尽（STED）和弹药显微镜。每种技术都将用于多种测定法中来研究结构急性γ辐射对唾液网格的功能后果。这是体外和体内实验通过长期协作将方法与计算建模结合使用。详细了解γ辐射对分泌的影响。以迭代方式，实验数据将是输入计算模型，随后用来做出进一步的预测，这些预测将是实验经过测试 - 进一步了解我们对唾液腺生理学和病理学的理解。在这些研究中，这是实验计算方法将用于确定唾液腺内部的变化如何影响它的功能，导致口干，事件永久性失去腺组织和功能。这个建议解决了可能决定这种功能丧失的三种不同机制。这些包括改变间隙和紧密连接，钙信号传导和线粒体生物能的功能。通过检查每个这些方面，实验数据可以集成到计算模型中。这个伟大的效用方法是，许多计算实验的迭代可以与这些体外同行完成和体内研究，并用于提出进一步的实验并做出预测。动态利用这种计算实验方法将有助于理解成分的变化 γ射线后，腺体的秘密机制可能会改变唾液的产生。最终，这种方法是旨在预测潜在的新型治疗方法来治疗γ辐射诱导的唾液功能障碍。