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

 描述(由申请者提供)：本次指导科学家奖(K01)申请的目标是促进申请者发展成为一名受过多学科培训的独立首席研究员。该应用程序的优势通过以下三个主要重点领域结合在一起。1)申请人的证件。Pi博士的申请建立在她之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。申请者的短期目标包括获得技术技能，启动和建立独立的研究领域，并提高专业技能(即科学写作、学员指导、补助金写作、口头交流)。长期目标集中在成为再生医学的领导者，获得终身教职的职位，培养未来的科学家，以及 参与社会和教职员工领导。2)培训环境。Pi博士得到了Bryon Petersen博士(导师)和Gregory Schultz博士(共同导师)的全力承诺和支持，以实施和完成提升优秀初级教师所需的培训。彼得森博士被公认为干细胞生物学和肝脏再生领域的世界领先者。 舒尔茨博士补充了候选人的新研究方向，带来了了解纤维化疾病机制的著名经验。由于勒文、斯里瓦斯塔瓦和高博士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博士选择了他们作为额外的成员。Pi博士将利用在获奖期间获得的结果，通过制定独立的New Investigator R01申请来证明并扩大项目的范围，以进入学术界的终身教职轨道职位。3)。创新模式和研究。有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变和肝癌。该提案的目的是了解酒精性肝病的分子机制，并确定逆转酒精性纤维化和预防肝硬变的治疗靶点。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的过度表达和转化生长因子(TGF)-？在多种纤维化疾病中均有发现。我们的研究发现CTGF是调节肝脏修复和肝祖细胞(HPC)激活的关键分子。我们已经开发了几种小鼠遗传工具，并将利用它们通过测试来确定CTGF在酒精性肝损伤中的功能：1)CTGF是否可以增强酒精性肝损伤早期的肝细胞损伤和炎症反应；2)CTGF是否在酒精性肝纤维化和HPC激活中发挥重要作用；3)通过RNA干扰和腺相关病毒(AAV)传递系统靶向CTGF和转化生长因子？是否可以减轻酒精性肝纤维化。该项目将采用多学科方法，包括肝脏病理生理学、AAV和基于RNA的疗法来检验中心假设。

 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.