Epigenetic Therapy to Treat Radiation-induced Xerostomia

表观遗传疗法治疗放射引起的口干症

基本信息

批准号：
10646364
负责人：
Isabelle M.A. Lombaert
金额：
$ 42.41万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646364
关键词：
AQP1 gene Adverse effects Affect CRISPR/Cas technology Capsid Cell Culture Techniques Cells Chronic Climacteric Clinical Clustered Regularly Interspaced Short Palindromic Repeats CpG Islands Cytosine DNA DNA Methylation DNA Sequence Data Dental caries Diagnosis Disease Dose Epigenetic Process Epithelial Cells Epithelium Exclusion Exposure to FDA approved Foundations Gene Expression Gene Silencing Gene Transfer Genes Gland Goals Grant Guide RNA Head and Neck Cancer Human Immune Immune Evasion Immune response Immunity In Vitro Inflammatory Response Mediator Messenger RNA Methods Methylation Miniature Swine Nature Non-Viral Vector Oral cavity Osmosis Pain Patients Phase Plasmids Production Promoter Regions Proteins RNA Radiation Radiation Dose Unit Radiation induced damage Radiation therapy Reporting Saliva Salivary Salivary Glands Speech Symptoms System Techniques Technology Testing Therapeutic Time Tissues Viral Viral Vector Water Water Movements Xerostomia bisulfite sequencing chromatin remodeling demethylation drinking water epigenetic therapy epigenome editing expression vector fitness gene therapy head and neck cancer patient histone modification in vivo interest next generation non-viral gene therapy oral infection overexpression palliative pre-clinical promoter regenerative regenerative therapy side effect success therapeutic gene tool transcriptome sequencing treatment planning ultrasound water channel whole genome

项目摘要

ABSTRACT Most head-and-neck cancer patients receiving radiotherapy treatment develop life-long adverse effects. Side effects presented as hyposalivation and chronic xerostomia result from radiation damage to nearby salivary glands. Limited palliative options are currently available for these patients, reinforcing the need for regenerative therapies. Our regenerative efforts, using non-viral gene therapy to overexpress water channel Aquaporin-1 (AQP1) in radiation-surviving salivary gland epithelial cells, showed restorative results by increasing salivary flow into the oral cavity. However, as both viral and non-viral vectors are restricted by the ability to provide long-term expression, a next generation of AQP1 therapy that results in sustained gene expression awaits. Our preliminary data demonstrates that methylation of the endogenous AQP1 promoter in epithelial cells is an important mediator of gene expression. In addition, the methylation status alters after exposure to radiation. Based on these findings, we hypothesize that epigenetic altering of the AQP1 promoter in radiation-surviving epithelial cells facilitates a change towards sustained endogenous AQP1 expression. To test this hypothesis, we adapted a new CRISPR method and aim to (1) demonstrate the negative correlation between the level of methylation and AQP1 expression, and (2) develop in vitro and in vivo methods to optimally alter the methylation level of the AQP1 promoter in irradiated epithelial cells. These studies bring in vivo epigenetic editing to a reality as a means of modulating endogenous gene expression and sustained water movement in damaged salivary glands. As a result, this continuous production of salivary flow can resolve xerostomia in radiated head-and-neck cancer patients in a long-term setting.