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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.

被诊断患有头颈癌的个体接受放射治疗作为标准治疗。然而,