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.

项目摘要： Tuo Shao，PhD是一名肝病学家，其总体职业目标是改善成果 通过开发提高诊断准确性和 将这些方法实施到临床实践中。他提出的研究名为“整合素 αVβ3临床前PET成像以检测早期纳什和治疗反应”，这 将物理评估与正电子发射断层扫描（PET）分子相结合 成像以识别非酒精性脂肪性肝炎（NASH），这将促进诊断和 患者NASH的治疗剂。这种识别将导致及时，准确的诊断 这将允许对该疾病的有针对性和有效管理。 候选人：Tuo Shao，PhD是哈佛医学院（HMS）医学研究员 以及马萨诸塞州一般医学和放射学系联合博士后研究员 医院（MGH）。他在路易斯维尔大学获得了药理学和毒理学博士学位 在开始MGH的博士后研究金之前。他以前的工作着重于 酒精性肝病（ALD）中肠道缺氧诱导因子1α（HIF-1α）。这项工作产生了 肝病学杂志的第一篇作者出版物。加入MGH后，Shao博士专注于肝 肝纤维化中的分子PET成像。这项工作导致了一份第一名的出版物， 文章被首席兼编辑肝病学杂志的编辑选为封面。 Shao博士 准备好在这里提出的科学和培训目的很充分的准备工作，并成功地 出版了七个第一或共同作者手稿和19篇合着者文章。 指导，培训活动和环境：Shao博士将进行拟议的项目 在MGH的史蒂文·梁（Steven Liang）的心态下，雷蒙德·T·钟（Raymond T. 艾伦·穆伦（Alan Mullen），医学博士，博士学位和王王（Changning Wang）博士。 Liang博士是NIH资助的科学家 放射性示意剂的开发和验证。 Chung博士是一位世界知名的NIH资助医师 临床和临床前肝病学的科学家成功地转介了几位K获奖者。 Wang博士是核医学专家。 Mullen博士是NIH资助的物理科学家 临床前肝纤维化，他是肝病分子生物学专家，他认为 许多博士后研究员和K-Awadees。 研究：非酒精性脂肪性肝炎（NASH）是慢性肝病的主要形式 西方世界被公认为是肝有关的发病率和死亡率的主要原因。肝 活检是诊断NASH的参考标准，但具有潜在并发症的侵入性。 玻璃蛋白受体整联蛋白αVβ3驱动肝星状细胞（HSC）的纤维化激活。 靶向整联蛋白αVβ3的分子成像可以提供一种无创的方法来评估 在受伤的激活HSC（AHSC）上整合素αVβ3的表达和功能 肝。在这项研究中，他感觉到比较[18f]/[68ga] - alfatide之间的差异 正常和NASH肝脏评估其用于评估NASH进展和治疗的实用性。 为了实现这一目标，他将用激活的HSC验证[18F] - alfatide的结合特征 体外研究（AIM 1）。然后，他将使用[18F]/[68GA] -Alfatide监视NASH的进展 不同的纤维化阶段（AIM 2）。最后，他将评估纳什和临床的恢复反应 使用[18F]/[68GA] -Alfatide/PET（AIM 3）翻译。完成此建议和培训计划 将Shao博士与至关重要的经验定位，成为一名独立的研究者 用肝病生物标志物分子宠物成像，这是一个无创的新兴领域 细胞和分子水平。