Integrin αvβ3 preclinical PET imaging to detect early stage NASH and treatment response

点击翻译按钮获取中文摘要

Project Summary: Tuo Shao, PhD is a hepatologist whose overarching career goal is to improve outcomes for patients with liver disease by developing methods to improve diagnostic accuracy and implementing these methods into clinical practice. The research he proposes entitled “Integrin αvβ3 preclinical PET imaging to detect early stage NASH and treatment response”, which combines physiological assessments with Positron emission tomography (PET) molecular imaging to identify nonalcoholic steatohepatitis (NASH), which will facilitate diagnosis and therapeutics for NASH in patients. Such identification will result in timely and accurate diagnosis that will permit targeted and effective management of this disease. Candidate: Tuo Shao, PhD is a research fellow in Medicine at Harvard Medical School (HMS) and joint postdoctoral fellow in Medicine and Radiology Department at Massachusetts General Hospital (MGH). He completed a Ph.D in Pharmacology and Toxicology at University of Louisville prior to beginning a postdoctoral fellowship at MGH. His previous work focusing on the role of intestinal hypoxia inducible factor-1α (HIF-1α) in alcoholic liver disease (ALD). This work resulted one first author publication in Journal of Hepatology. After joined MGH, Dr.Shao focus on hepatic molecular PET imaging in liver fibrosis. This work resulted in one first-author publication and the article was selected as cover by editor of chief and co-editors of Journal of Hepatology. Dr. Shao is well-prepared to undertake the scientific and training aims proposed here, having successfully published seven first or co-first-author manuscripts and 19 co-author articles. Mentorship, Training Activities, and Environment: Dr. Shao will conduct the proposed project at MGH under the mentorship of Steven Liang, PhD and co-mentorship of Raymond T. Chung, Alan Mullen, MD, PhD and Changning Wang, PhD. Dr. Liang is a NIH-funded scientist in radiotracer development and validation. Dr. Chung is a world-renowned, NIH-funded physician scientist in clinical and preclinical hepatology, who has successfully mentored several K awardees. Dr. Wang is a is a nuclear medicine specialist. Dr. Mullen is a NIH-funded physician scientist in preclinical liver fibrosis, he is an expert in molecular biology of liver disease, he has mentored many postdoctoral fellows and K-awardees. Research: Nonalcoholic steatohepatitis (NASH) is a major form of chronic liver disease in the Western world, is recognized as a major cause of liver-related morbidity and mortality. Liver biopsy is the reference standard to diagnose NASH but is invasive with potential complications. The vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, he sought to compare differences in the uptake of [18F]/[68Ga]-Alfatide between normal and NASH liver to evaluate its utility for assessment of NASH progression and treatment. To achieve this goal, he will validate binding characteristics of [18F]-Alfatide with activated HSCs in vitro studies (Aim 1). Then, he will use [18F]/[68Ga]-Alfatide to monitor NASH progression at different fibrosis stage (Aim 2). Finally, he will assess the recovery response of NASH and clinical translation using [18F]/[68Ga]-Alfatide/PET (Aim 3). Completion of this proposal and training plan will position Dr. Shao with the vital experience to become an independent investigator combining molecular PET imaging with liver disease biomarkers, an emerging field of noninvasive at the cellular and molecular level.