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

• 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
• 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

 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.

 该指导科学家奖（K 01）申请的目标是促进申请人发展成为一名多学科培训的独立主要研究者。该应用程序的优势是由以下三个重点领域汇集在一起。1)申请人的证书。皮博士的申请建立在她以前的生产力记录的基础上，集中决心通过改变研究方向来建立科学独立性。申请人的短期目标包括获得技术技能，启动和建立一个独立的研究路线，并提高专业技能（即科学写作，指导学员，赠款写作，口头交流）。长期目标是成为再生医学的领导者，实现终身职位，培养未来的科学家， 参与社会和教师领导。2)训练环境。Pi博士得到了Bryon Petersen博士（导师）和Gregory Schultz博士（共同导师）的全力支持，以实施和完成必要的培训，以促进优秀的初级教师。彼得森博士被公认为干细胞生物学和肝再生领域的世界领导者。 博士舒尔茨补充了候选人的新的研究方向，带来了著名的经验，了解纤维化疾病的机制。皮博士选择Lewin博士、Srivastava博士和Gao博士作为额外成员，因为他们在培养下一代成功的学术科学家方面的卓越承诺和经验。Pi博士将利用在获奖期间获得的结果，通过制定独立的新研究者R 01申请来证明和扩大项目的范围，以推进学术界的终身职位。3）。创新模式和研究。待检验的中心假设是：“结缔组织生长因子（CTGF）是酒精性肝病（ALD）的重要治疗靶点。“ALD的范围包括脂肪性肝炎、纤维化到终末期肝硬化和肝癌。该提案的目标是了解ALD的分子机制，并确定逆转酒精性纤维化和预防肝硬化的治疗靶点。到目前为止，还没有FDA批准的任何纤维化疾病的治疗方法。CTGF过表达与转化生长因子（TGF）-β共同存在于多种纤维化疾病中。我们的研究已经确定CTGF是调节肝修复和肝祖细胞（HPC）活化的关键分子。我们已经开发了几种遗传小鼠工具，并将使用它们来确定CTGF在ALD中的功能，通过测试：1）CTGF是否在酒精性肝损伤的早期阶段增强肝细胞损伤和炎症; 2）CTGF是否在酒精性肝纤维化和HPC活化的进展中起重要作用; 3）利用RNA干扰和腺相关病毒（AAV）递送系统靶向CTGF和TGF-β是否减少酒精性纤维化。该项目将采用多学科的方法，包括肝脏病理生理学，AAV和RNA为基础的治疗来测试中心假设。