Connective tissue growth factor: an intriguing therapeutic target in alcoholic liver disease

结缔组织生长因子：酒精性肝病的一个有趣的治疗靶点

基本信息

批准号：
9210038
负责人：
Liya Pi
金额：
$ 14.51万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210038
关键词：
Academia Acceleration Acute Affect Alcoholic Liver Diseases Alcohols American Area Award Binding Carbon Tetrachloride Cell Surface Proteins Cells Cessation of life Chronic Cicatrix Cirrhosis Collagen Type I Complement Cues DNA cassette Data Dependovirus Development Diagnosis Diet Disease Disease Progression Enhancers Environment Ethanol FDA approved Faculty Fibrosis Functional disorder Future Gene Expression Genes Genetic Goals Grant Growth Factor Health Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Hepatitis Hepatocyte In Vitro Inflammation Inflammatory Injury Integrins Intoxication Knock-out Knockout Mice Knowledge Kupffer Cells Leadership Left Liquid substance Liver Liver Failure Liver Fibrosis Liver Regeneration Malignant neoplasm of liver Mediating Mentors MicroRNAs Modeling Molecular Morbidity - disease rate Mus Myofibroblast Patients Phase Play Positioning Attribute Principal Investigator Production Productivity Proteins RNA RNA Interference Reaction Recombinant adeno-associated virus (rAAV)Recruitment Activity Regenerative Medicine Regulation Research Research Personnel Role Scientist Small Interfering RNA Smooth Muscle Actin Staining Method Societies Source Steatohepatitis Stem cells System Technical Expertise Techniques Testing Therapeutic Therapeutic Intervention Training Transforming Growth Factors Virus Diseases Writing base chronic alcohol ingestion chronic liver disease connective tissue growth factor design experience feeding follow-up gene therapy hepatotoxin in vivo inhibitor/antagonist innovation interdisciplinary approach knock-down knockout gene liver cell proliferation liver function liver injury liver repair member mortality mouse model next generation oral communication overexpression polarized cell prevent problem drinker public health relevance regenerative response skills stem cell biology targeted treatment tenure track therapeutic target tissue repair tool viral RNA

项目摘要

DESCRIPTION (provided by applicant): The goal of this Mentored Scientist Award (K01) application is to promote the development of the applicant into a multi-disciplinarily trained independent principal investigator. The strengths of the application are brought together by three major areas of emphasis as follows. 1) Credentials of the applicant. Dr. Pi's application builds upon her previous track-record of productivity with a concentrated determination to establish scientific independence through a change in research direction. The applicant's short-term goals encompass the acquisition of technical skills, initiation and establishment of an independent line of research, and to enhance professional skills (i.e. scientific writing, mentorin of trainees, grant writing, oral communication). Long-term goals are centered on becoming a leader in regenerative medicine, achieving a tenure-track position, training future scientists, and involvement in society and faculty leadership. 2) Training environment. Dr. Pi has received full commitment and the support of Drs. Bryon Petersen (mentor) and Gregory Schultz (co-mentor) to implement and complete the training necessary to advance outstanding junior faculty. Dr. Petersen is recognized as a world leader in the fields of stem cell biology and liver regeneration. Dr. Schultz complements the candidate's new direction of research by bringing renowned experience of understanding mechanism of fibrotic disorders. Dr. Pi has selected Drs. Lewin, Srivastava, and Gao as additional members due to their remarkable commitment and experience in developing the next generation of successful academic scientists. Dr. Pi will use the results obtained during the award period to justify and extend the scope of the project by formulating an independent New Investigator R01 application to advance into a tenure track position in academia. 3). Innovative models and research. The central hypothesis to be tested is that: "Connective tissue growth factor (CTGF) is an important therapeutic target for alcoholic liver disease (ALD)." The spectrum of ALD encompasses steatohepatitis, fibrosis to end-stage cirrhosis and liver cancer. The goal of this proposal is to understand the molecular mechanism of ALD and identify therapeutic targets that reverse alcoholic fibrosis and prevent cirrhosis. So far, there is no FDA approved treatment for any fibrotic disorder. CTGF overexpression, together with transforming growth factor (TGF)-ß, has been found in various kinds of fibrotic disorders. Our research has identified CTGF as a key molecule in the regulation of liver repair and hepatic progenitor cell (HPC) activation. We have developed several genetic mouse tools and will use them to determine the function of CTGF in ALD by testing: 1) whether CTGF can potentiate hepatocyte injury and inflammation during the early phase of alcoholic liver injury; 2) whether CTGF plays an important role in progression of alcoholic fibrosis and HPC activation; 3) whether targeting CTGF and TGF-ß utilizing RNA interference and adeno- associated virus (AAV) delivery system reduces alcoholic fibrosis. This project will employ a multidisciplinary approach, including liver pathophysiology, AAV and RNA-based therapies to test the central hypothesis.

描述（由应用程序提供）：该指导科学家奖的目标（K01）的申请是将应用程序的开发促进了经过多学科培训的独立首席研究员的开发。该应用的优势由三个主要的重点领域汇总在一起，如下所示。 1）应用程序的凭据。 Pi博士的应用基于她以前的生产力纪录，并坚定决心通过改变研究方向建立科学独立性。申请人的短期目标包括获得独立研究线的技术技能，主动性和建立，并提高专业技能（即科学写作，学员的精神，赠款写作，口头交流）。长期目标集中在成为再生医学的领导者，获得终身制职位，培训未来的科学家和参与社会和教师领导。 2）培训环境。 PI博士已得到充分的承诺和Drs的支持。布莱恩·彼得森（Bryon Petersen）（导师）和格雷戈里·舒尔茨（Gregory Schultz）（同事），以实施并完成必要的培训，以促进出色的初级教师。彼得森博士被认为是干细胞生物学和肝脏再生领域的世界领导者。舒尔茨博士通过带来著名的了解纤维化疾病机制的经验来遵守候选人的新研究方向。 Pi博士因其在发展下一代成功的学术科学家方面的非凡承诺和经验，因此选择了Lewin，Srivastava和Gao作为其他成员。 PI博士将利用奖励期间获得的结果来证明和扩展项目范围，通过制定独立的新调查员R01申请，以晋升为学术界的终身轨道职位。 3）。创新模型和研究。要测试的中心假设是：“结缔组织生长因子（CTGF）是酒精性肝病（ALD）的重要治疗靶标。” ALD的光谱包括脂肪性肝炎，纤维化与终末期和肝癌。该建议的目的是了解ALD的分子机制，并确定逆转酗酒纤维化并预防肝硬化的治疗靶标。到目前为止，尚未针对任何纤维化疾病获得FDA批准的治疗方法。 CTGF的过表达以及转化的生长因子（TGF）-ß已在各种纤维化疾病中发现。我们的研究已将CTGF确定为调节肝修复和肝祖细胞（HPC）激活的关键分子。我们已经开发了几种遗传小鼠工具，并将通过测试来确定CTGF在ALD中的功能：1）CTGF是否可以在酒精性肝损伤的早期阶段潜在潜在的肝细胞损伤和炎症； 2）CTGF是否在酒精纤维化和HPC激活的进展中起重要作用； 3）靶向CTGF和TGF-ß是否利用RNA干扰和腺相关病毒（AAV）递送系统降低了酒精性纤维化。该项目将采用多学科方法，包括肝脏病理生理学，基于AAV和基于RNA的疗法来检验中心假设。