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

整合素αvβ3 临床前 PET 成像检测早期 NASH 和治疗反应

• 批准号: 10449428
• 负责人: Tuo Shao
• 金额: $ 15.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449428
• 关键词: Affinity; Alcoholic Liver Diseases; Animal Model; Animals; Apoptosis; Autoradiography; Binding; Biodistribution; Biological Markers; Carbon Tetrachloride; Cell Adhesion; Cells; Characteristics; Clinical; Clinical Trials; Collagen; Data; Development; Diagnosis; Diet; Discipline of Nuclear Medicine; Disease; Disease Management; Doctor of Philosophy; Early Diagnosis; Environment; Etiology; Event; Extracellular Matrix Proteins; Fellowship; Fibrosis; Funding; General Hospitals; Goals; Gold; Hepatic; Hepatic Stellate Cell; Hepatology; Histopathology; Human; Hypoxia Inducible Factor; Imaging Techniques; In Vitro; Individual; Integrin Binding; Integrin alphaVbeta3; Joints; Journals; Knowledge; Label; Ligation; Liver; Liver Fibrosis; Liver diseases; Manuscripts; Massachusetts; Medicine; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Monitor; Morbidity - disease rate; Mus; Myofibroblast; Patient-Focused Outcomes; Patients; Pharmacology and Toxicology; Physicians; Physiological; Play; Positioning Attribute; Positron-Emission Tomography; Postdoctoral Fellow; Prognosis; Publications; Publishing; Radiology Specialty; Recovery; Reference Standards; Research; Research Personnel; Role; Scientist; Severities; Signal Transduction; Smooth Muscle Actin Staining Method; Specialist; Therapeutic; Time; Tissues; Training; Training Activity; Translations; United States National Institutes of Health; Universities; Validation; Vitronectin Receptors; Western World; Work; accurate diagnosis; base; bile duct; biomarker development; career; career development; chronic liver disease; clinical practice; clinical translation; clinically translatable; diagnostic accuracy; experience; fibrogenesis; human study; improved; improved outcome; in vivo; intestinal hypoxia; liver biopsy; liver injury; medical schools; molecular imaging; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; pre-clinical; radiotracer; response; simple steatosis; skill acquisition; skills; targeted imaging; therapeutically effective; treatment response; uptake; validation studies

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.

项目概要： 邵拓博士是一位肝病专家，其首要职业目标是改善患者的治疗结果 通过开发方法来提高诊断准确性和肝病患者 将这些方法应用到临床实践中。他提出的研究题为“整合素 αvβ3 临床前 PET 成像可检测早期 NASH 和治疗反应”， 将生理评估与正电子发射断层扫描 (PET) 分子相结合 影像学检查可识别非酒精性脂肪性肝炎 (NASH)，这将有助于诊断和治疗 NASH 患者的治疗方法。这样的识别将导致及时、准确的诊断 这将有助于有针对性地、有效地管理这种疾病。 候选人：邵拓博士，哈佛医学院（HMS）医学研究员 马萨诸塞州总医院医学和放射学系联合博士后研究员 医院（麻省总医院）。他在路易斯维尔大学获得了药理学和毒理学博士学位 在 MGH 开始博士后研究之前。他之前的作品重点关注角色 酒精性肝病（ALD）中的肠道缺氧诱导因子-1α（HIF-1α）。这项工作产生了 《肝病学杂志》上的一篇第一作者论文。加入麻省总医院后，邵博士专注于肝脏 肝纤维化的分子 PET 成像。这项工作产生了一份第一作者出版物，并 文章被《Journal of Hepatology》主编和联合主编选为封面。邵博士 已做好充分准备来实现此处提出的科学和培训目标，并已成功 发表第一或共同第一作者手稿 7 篇，共同作者文章 19 篇。 指导、培训活动和环境：邵博士将主持拟议的项目 在麻省总医院 (MGH) 的指导下，史蒂文·梁 (Steven Liang) 博士和雷蒙德·钟 (Raymond T. Chung) 共同指导， Alan Mullen（医学博士）和 Wang Changning（王长宁）博士。梁博士是 NIH 资助的科学家 放射性示踪剂的开发和验证。 Chung 博士是一位世界知名、由 NIH 资助的医生 临床和临床前肝病学科学家，成功指导了几位 K 获奖者。 王医生是一位核医学专家。 Mullen 博士是 NIH 资助的医学科学家 临床前肝纤维化，他是肝病分子生物学专家，曾指导过 许多博士后研究员和 K 奖获得者。 研究：非酒精性脂肪性肝炎（NASH）是慢性肝病的一种主要形式 西方世界，被认为是肝脏相关发病和死亡的主要原因。肝 活检是诊断 NASH 的参考标准，但具有侵入性，存在潜在的并发症。 玻连蛋白受体整合素 αvβ3 驱动肝星状细胞 (HSC) 的纤维化激活。 针对整合素αvβ3的分子成像可以提供一种非侵入性的评估方法 损伤者激活的HSCs（aHSCs）上整合素αvβ3的表达和功能 肝。在这项研究中，他试图比较 [18F]/[68Ga]-Alfatide 的摄取差异 正常和 NASH 肝脏，以评估其在评估 NASH 进展和治疗方面的效用。 为了实现这一目标，他将验证 [18F]-Alfatide 与激活的 HSC 的结合特性 体外研究（目标 1）。然后，他将使用 [18F]/[68Ga]-Alfatide 监测 NASH 进展 不同的纤维化阶段（目标 2）。最后，他将评估 NASH 的恢复反应和临床情况 使用 [18F]/[68Ga]-Alfatide/PET 进行翻译（目标 3）。完成本提案及培训计划 将为邵博士提供成为一名独立研究者的重要经验，结合 肝病生物标志物的分子 PET 成像，这是非侵入性的新兴领域 细胞和分子水平。