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： Tuo Shao博士是一名肝病学家，其首要职业目标是改善 肝病患者通过开发方法来提高诊断准确性， 将这些方法应用于临床实践。他提出的题为“整合素 αvβ3临床前PET成像检测早期NASH和治疗反应”， 将生理评估与正电子发射断层扫描（PET）分子 成像以识别非酒精性脂肪性肝炎（NASH），这将有助于诊断， NASH患者的治疗方法。这种识别将导致及时和准确的诊断 这将有助于对这一疾病进行有针对性的有效管理。 候选人：邵拓博士是哈佛医学院（HMS）的医学研究员。 马萨诸塞州总医院医学和放射学系博士后研究员 医院（MGH）。他在路易斯维尔大学完成了药理学和毒理学博士学位 在开始在MGH博士后奖学金之前。他以前的工作重点是 肠缺氧诱导因子-1 α（HIF-1α）在酒精性肝病（ALD）中的作用这项工作导致 在Journal of Hepatology上发表了一篇第一作者论文。加入MGH后，邵医生专注于肝脏 肝纤维化的分子PET成像这项工作导致了一个第一作者出版物和 文章被《肝病学杂志》主编和合作编辑选作封面。邵医生 已做好充分准备，承担这里提出的科学和培训目标，成功地 发表了7篇第一作者或共同第一作者的手稿和19篇共同作者的文章。 指导、培训活动和环境：邵博士将指导拟议的项目 在MGH，由Steven Liang博士指导，Raymond T.阿忠， Alan马伦，医学博士，博士和Changning Wang，博士。梁博士是美国国立卫生研究院资助的科学家， 放射性示踪剂的开发和验证。钟博士是一位世界知名的，NIH资助的医生 临床和临床前肝病学科学家，他成功指导了几位K获奖者。 博士王先生是一位核医学专家。马伦博士是美国国立卫生研究院资助的内科科学家， 临床前肝纤维化，他是肝病分子生物学专家，他指导了 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， 在西方世界，被认为是肝脏相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。 玻连蛋白受体整合素αvβ3驱动肝星状细胞（HSC）的纤维化活化。 以整合素αvβ3为靶点的分子影像学检查可为临床提供一种非侵入性的方法， 损伤后活化的肝星状细胞（aHSCs）整合素αvβ3的表达及功能 肝脏在这项研究中，他试图比较在[18 F]/[68 Ga]-阿尔法肽摄取方面的差异， 正常肝脏和NASH肝脏，以评价其用于评估NASH进展和治疗的效用。 为了实现这一目标，他将验证[18 F]-阿尔法肽与活化的HSC的结合特性 体外研究（目标1）。然后，他将使用[18F]/[68 Ga]-阿尔法肽监测NASH进展， 不同纤维化分期（目的2）。最后，他将评估NASH的恢复反应和临床 使用[18F]/[68 Ga]-阿尔法肽/PET进行翻译（Aim 3）。完成本建议书和培训计划 将邵博士的重要经验，成为一个独立的研究者， 分子PET成像与肝病生物标志物，一个新兴的领域， 细胞和分子水平。