Targeting the DNA damage response pathway for the treatment of HSV esophagitis

靶向DNA损伤反应途径治疗HSV食管炎

基本信息

批准号：
8474598
负责人：
Oleg Alekseev
金额：
$ 4.72万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-07 至 2016-05-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8474598
关键词：
AIDS/HIV problem Academic Medical Centers Acquired Immunodeficiency Syndrome Acyclovir Address Affect Antiviral Agents Area Basic Science Cancer Patient Cells Chromatin Clinical Clinical Medicine Cornea DNA Damage Data Discipline Disease Doctor of Philosophy Encephalitis Environment Epithelial Epithelial Cells Epithelium Esophageal Esophageal mucous membrane Esophagitis Esophagus Euchromatin Event Faculty Fellowship Gastroenterology Gastrointestinal tract structure Genome Goals Hemorrhage Herpes Esophagitis Herpes Labialis Herpesvirus 1 Immunocompromised Host In Vitro Incidence Infection Internal Medicine Invaded Investigation Keratoconjunctivitis Lead Learning Liver Lytic Lytic Phase Modeling Molecular Mus Neurons Nodose Ganglion Nuclear Organ Transplantation Pathology Pathway interactions Patients Phase Phosphorylation Phosphotransferases Population Positioning Attribute Recurrence Reporting Research Research Design Research Training Residencies Resistance Role Scientist Sensory Ganglia Simplexvirus Site Source Stress Students Surface System Testing Training Translating Transplant Recipients Ulcer Vagus nerve structure Viral Virion Virus Virus Activation Virus Diseases Work ataxia telangiectasia mutated protein base cellular targeting chromatin remodeling clinically significant experience fascinate gastrointestinal human disease in vitro Model in vivo inhibitor/antagonist migration new therapeutic target painful swallowing particle pathogen reactivation from latency research study resistant strain response sensor small molecule therapeutic target training project virus host interaction

项目摘要

DESCRIPTION (provided by applicant): As an MD/PhD student, my goal is to work at the interface of basic research and clinical medicine. I am fascinated by the molecular controls of cellular responses to environmental events, such as infection by a pathogen or damage from an exogenous source. Understanding these responses may lead to new therapies for a variety of diseases. The GI tract and liver are intriguing systems as they are constantly exposed to a variety of pathogens. The clinical discipline of gastroenterology is fascinating and has many areas open to investigation. I envision myself as primarily a research scientist at an academic medical center, but with the added benefit of learning from my patients and perhaps translate my experiments to treatments. The proposed project and training plan will provide me training in hypothesis-driven research design and interpretation. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that causes a wide range of human disease, including such well-known conditions as cold sores, keratoconjunctivitis, and encephalitis. HSV-1 has an expanded spectrum of pathologies in immunocompromised patients (e.g. organ transplant recipients and AIDS and cancer patients) who often experience gastrointestinal (GI) manifestations of this virus. While HSV-1 is able to invade most mucocutaneous surfaces, the most common GI site of infection is the esophagus, where HSV-1 frequently causes recurrent epithelial ulceration. The estimates of the incidence of herpes esophagitis vary widely, with some studies reporting as much as 15% of transplant recipients testing positive. Herpes esophagitis usually presents as a reactivation from latency in the nodose ganglion of the vagus nerve. Despite the significance of this clinical problem, research toward understanding the molecular mechanisms of virus- host interactions in esophageal epithelial remains inadequate. HSV-1 interacts with host cells on the molecular level, presumably to optimize its environment for the specific phase of its lifecycle. One of the pathways activated by HSV-1 is the DNA damage response (DDR), initiated by the phosphorylation of a sensor kinase ataxia telangiectasia mutated (ATM). Activated ATM and other DDR components co-localize to the viral replication compartments during lytic infection. Furthermore, in neurons, which lack nuclear ATM and Chk2 and are incapable of mounting a DDR, HSV-1 infection is typically latent. In preliminary studies in corneal and esophageal cells, we have found that inhibition of ATM or the downstream Chk2 kinase leads to greatly reduced viral replication,. Based on these observations, we hypothesize that activation of ATM and the DDR by HSV-1 is a switch to allow for productive infection. The goal of this proposal is to utilize in vitro and in vivo experiments to identify the mechanism by which HSV-1 activates ATM in esophageal epithelial cells and to elucidate the role of DDR in the lifecycle of HSV-1. These studies will impact our understanding of the molecular pathways underlying HSV-1 infection and reactivation from latency, potentially identifying novel therapeutic targets for the treatment of herpes esophagitis.

描述（由申请人提供）：作为MD/PhD学生，我的目标是在基础研究和临床医学的界面上工作。我对细胞对环境事件的分子反应的分子控制着迷，例如病原体感染或外源性来源的损害。了解这些反应可能会导致各种疾病的新疗法。胃肠道和肝脏是引人入胜的系统，因为它们不断暴露于各种病原体。胃肠病学的临床学科令人着迷，并且有许多领域可以进行调查。我认为自己主要是一个学术医学中心的研究科学家，但要向患者学习，也许将我的实验转化为治疗。拟议的项目和培训计划将为我提供假设驱动的研究设计和解释的培训。单纯疱疹病毒1（HSV-1）是一种普遍存在的病原体，可引起广泛的人类疾病，包括诸如唇疱疹，角膜结膜炎和脑炎等众所周知的疾病。 HSV-1在免疫功能低下的患者（例如器官移植受者，艾滋病和癌症患者）中的病理范围扩大，这些患者经常经历该病毒的胃肠道（GI）表现。尽管HSV-1能够侵入大多数粘膜表面，但最常见的GI感染部位是食管，HSV-1经常引起复发性上皮溃疡。疱疹性食管炎发病率的估计值差异很大，一些研究报告了多达15％的移植受者测试阳性。疱疹食管炎通常是从迷走神经的鼻神经节中潜伏的重新激活。尽管这个临床问题具有重要意义，但研究对了解食管上皮中病毒宿主相互作用的分子机制的研究仍然不足。 HSV-1在分子水平上与宿主细胞相互作用，大概是为了优化其生命周期特定阶段的环境。由HSV-1激活的途径之一是DNA损伤反应（DDR），该途径是由传感器激酶temaxia telangictia突变（ATM）的磷酸化引发的。活化的ATM和其他DDR组件在裂解感染过程中将其定位到病毒复制区。此外，在缺乏核ATM和CHK2并且无法安装DDR的神经元中，HSV-1感染通常是潜在的。在角膜和食管细胞的初步研究中，我们发现抑制ATM或下游CHK2激酶会大大降低病毒复制。基于这些观察结果，我们假设HSV-1的ATM和DDR激活是允许生产性感染的转换。该提议的目的是利用在体外和体内实验，以确定HSV-1激活食管上皮细胞中ATM的机制，并阐明DDR在HSV-1生命周期中的作用。这些研究将影响我们对HSV-1感染的分子途径的理解和潜伏期的重新激活，这可能鉴定出用于治疗疱疹性食管炎的新型治疗靶标。