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.

项目总结： 邵拓博士是一位肝病学家，他的首要职业目标是改善治疗结果 通过开发方法来提高肝病患者的诊断准确率和 将这些方法应用于临床实践。他提出的题为“整合素”的研究 αvβ3临床前正电子发射计算机断层扫描检测早期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 成像识别非酒精性脂肪性肝炎(NASH)，这将有助于诊断和 NASH患者的治疗学。这样的识别将导致及时和准确的诊断 这将使有针对性和有效地管理这种疾病成为可能。 候选人：邵拓，博士，哈佛医学院医学研究员 马萨诸塞州总医院医学和放射科联合博士后研究员 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 在开始麻省理工学院博士后奖学金之前。他之前的工作重点是 低氧诱导因子-1α在酒精性肝病中的表达及意义这项工作的结果是 第一作者发表在《肝病杂志》上。加入MGH后，邵逸夫主攻肝脏 分子PET成像在肝纤维化中的应用这项工作导致了一本第一作者的出版物和 文章被《肝病杂志》主编和联合主编选为封面。邵大夫 已做好充分准备，以实现这里提出的科学和培训目标，并已成功 发表了7篇第一作者或合著者手稿和19篇合著者文章。 导师、培训活动和环境：邵逸夫博士将领导拟议的项目 在MGH，在梁世华博士的指导下和钟庭耀的共同指导下， 艾伦·马伦，医学博士，王昌宁博士。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。钟医生是美国国立卫生研究院资助的世界知名内科医生。 临床和临床前肝病学科学家，他成功地指导了几位K奖获得者。 王医生是一名核医学专家。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的专家，他曾指导 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，被认为是与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，但具有侵袭性，有潜在的并发症。 Vitronectin受体整合素αvβ3驱动肝星状细胞(HSC)的纤维化活化。 针对整合素αvβ3的分子成像可以提供一种非侵入性的检测方法 损伤后活化的肝星状细胞整合素αvβ3的表达及其作用 肝脏。在这项研究中，他试图比较两种药物对[18F]/[68Ga]-Alfolde摄取的差异 以评估其在评估NASH进展和治疗方面的作用。 为了实现这一目标，他将验证[18F]-Alfolde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在以下位置监控纳什进展 不同纤维化阶段(目标2)。最后，他将评估纳什和临床的康复反应 使用[18F]/[68Ga]-Alfolde/PET进行翻译(目标3)。完成本建议书和培训计划 我将让邵逸夫拥有成为独立调查员的重要经验 应用肝病生物标志物的分子PET成像--一个新兴的非侵入性研究领域 细胞和分子水平。