Whole Body Imaging of Beta Cell Mass in Diabetes

描述(由申请人提供)：这项提议的广泛目标是开发具有临床翻译潜力的小鼠的β细胞团(BCM)的非侵入性全身成像。这些药物将用于研究I型糖尿病在各种小鼠模型中的进展，以阐明疾病的病因和进展。候选人格雷格·瑟伯在了解显像剂的分布和药代动力学方面拥有丰富的经验，他将把这些技能应用于设计新的显像剂和量化BCM。BCM显像剂的研制成功将为糖尿病的研究领域做出重大贡献，极大地促进糖尿病的诊断、进展和治疗干预。候选人的长期目标是开发新的成像试剂，以解决糖尿病研究中的重要生物学问题。这项工作将在哈佛/麻省理工学院系统生物学中心进行，由Ralph Weissleder博士博士指导。由于候选人在T32培训中与这位导师合作，他还请来了Diane Mathis博士和Christophe Benoist博士，这两位都是糖尿病研究的专家，以获得更多的指导和专业知识。马塞洛·迪卡利医学博士在深入了解临床翻译方面的支持也将包括在候选人的培训中。咨询委员会的这些成员将促进候选人的工作从主要导师过渡到作为独立糖尿病研究人员发展成功的职业生涯。这项建议的具体目标是首先开发一种具有优化性能的β细胞显像剂，用于全身成像，然后在各种动物模型中进行体内成像。这项工作源于使用exendin衍生物对β细胞胰岛进行活体显微镜的初步研究。这些探针对体内荧光成像具有最佳的药代动力学，但对全身成像的额外限制，如靶外摄取和放射化学合成，使这些探针变得不理想。广泛的药代动力学模拟表明，通过延长血浆半衰期和减少剂量，可以改善靶背景比，提高检测的灵敏度。此外，这些模拟还指出了在因炎症而导致的可变递送情况下对BCM进行量化所需的剂量和成像时间点。特殊目的1将开发基于Exendin多肽的新型探针，通过聚乙二醇化和/或特定白蛋白结合肽减少血浆清除量来靶向β细胞。这是一种有效的延长血浆半衰期和减少肾脏摄取的方法，并将利用广泛的体外和体内试验来确保足够的靶向性。特殊目标2将利用新的四嗪和反环辛烯化学来快速放射性标记来自目标1的新探针，用于活体非侵入性成像。用于研究1型糖尿病的各种新的动物模型将用新的探针进行成像，以测试成像信号对合并炎症的不同BCM的敏感性。如果成功，这些试剂将允许对任何动物疾病模型的BCM进行纵向非侵入性成像，并可用于监测进展和测量治疗干预。此外，全身成像使这些试剂有可能在临床上转化为监测患者的BCM。 公共卫生相关性：该项目旨在创建用于监测I型糖尿病进展的新型显像剂。如果成功，这些试剂将允许在有更多治愈治疗潜力的地方更早地诊断疾病，允许治疗监测，并为确定新疗法的有效性提供更好的工具。

DESCRIPTION (provided by applicant): The broad goal of this proposal is to develop non-invasive whole body imaging of beta cell mass (BCM) in mice with the potential for clinical translation. These agents will be used to study the progression of type I diabetes mellitus in a variety of mouse models to elucidate the etiology and progression of the disease. The candidate, Greg Thurber, has extensive experience in understanding the distribution and pharmacokinetics of imaging agents and will apply these skills to design novel agents and quantify BCM. The successful development of an imaging agent for measuring BCM would make a substantial contribution to the field of diabetes research, greatly facilitating the diagnosis, progression, and treatment intervention for the disease. The long term goal of the candidate is to develop novel imaging agents to address important biological questions in diabetes research. This work will be conducted in the Harvard/MGH Center for Systems Biology under the mentorship of Dr. Ralph Weissleder MD PhD. Since the candidate has worked with this mentor for his T32 training, he has also brought on Dr. Diane Mathis PhD and Dr. Christophe Benoist MD PhD, both experts in diabetes research, for additional mentoring and expertise. The support of Dr. Marcelo Di Carli MD in gaining insight into clinical translation will also be included in the candidate's training. These members of the advisory committee will facilitate the transition of the candidate's work away from the primary mentor to develop a successful career as an independent diabetes researcher. The specific aims of this proposal first develop a beta cell imaging agent with optimized properties for whole body imaging followed by in vivo imaging in a variety of animal models. This work stems from preliminary research using exendin derivatives for intravital microscopy of beta cell islets. These probes have optimal pharmacokinetics for in vivo fluorescence imaging, but the additional constraints for whole body imaging, such as off target uptake and radiochemical synthesis, make these probes non-ideal. Extensive pharmacokinetic simulations show that by extending the plasma half life and reducing the dose, the target to background ratio can be improved, increasing the sensitivity of detection. Additionally, the simulations indicate the doses and imaging time points required for quantitating BCM in the context of variable delivery due to inflammation. Specific aim 1 will develop novel probes based on the exendin peptide for beta cell targeting by reducing plasma clearance through PEGylation and/or specific albumin binding peptides. This is a well validated method for extending plasma half life and reducing renal uptake, and extensive in vitro and in vivo testing will be utilized to ensure adequate targeting. Specific aim 2 will utilize novel tetrazine and trans-cyclo- octene chemistry to rapidly radiolabel the novel probes from aim 1 for in vivo non-invasive imaging. A variety of novel animal models for studying type 1 diabetes will be imaged with the novel probes to test the sensitivity of imaging signal to varying BCM with concurrent inflammation. If successful, these agents will allow longitudinal non-invasive imaging of BCM for any animal model of disease and can be used for monitoring progression and measuring therapeutic intervention. Furthermore, the whole body imaging enables the possible clinical translation of these agents for monitoring BCM in patients. PUBLIC HEALTH RELEVANCE: This project aims to create novel imaging agents for monitoring the progression of type I diabetes. If successful, these agents will allow earlier diagnosis of the disease where there is more potential for curative treatment, allow treatment monitoring, and provide a better tool for determining the effectiveness of new therapies.