Whole Body Imaging of Beta Cell Mass in Diabetes

糖尿病β细胞团的全身成像

基本信息

批准号：
8224516
负责人：
Greg Thurber
金额：
$ 16.02万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2012-07-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8224516
关键词：
Accounting Address Advisory Committees Affinity Aging Albumins Animal Disease Models Animal Model Antigens Beta Cell Binding Biodistribution Biological Calibration Cell Line Cells Chemistry Clinic Clinical Data Detection Development Diabetes Mellitus Diagnosis Disease Disease Progression Doctor of Philosophy Dose Drug Kinetics Early Diagnosis Effectiveness Ensure Etiology Exocrine pancreas Generations Goals Gold Half-Life Image Immune Immunology In Vitro Individual Inflammation Insulin-Dependent Diabetes Mellitus Intervention Kidney Kinetics Label Literature Liver Measurement Measures Mentors Mentorship Methods Microscopic Modification Molecular Weight Monitor Mus Organ Pancreas Patients Peptides Pharmaceutical Preparations Plasma Positron-Emission Tomography Property Radiolabeled Reporting Research Research Design Research Personnel Resolution SECTM1 gene Sensory Receptors Series Signal Transduction Specificity Sulfonylurea Compounds Systems Biology Testing Therapeutic Intervention Time Toxic effect Training Translating Translations Work analog base career cellular imaging cycloaddition design experience fluorescence imaging imaging probe improved in vivo insight intravital microscopy islet member molecular imaging mouse model novel pharmacokinetic model radiochemical radiotracer research study scaffold simulation skills stem success tool uptake whole body imaging

项目摘要

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.

描述（由申请人提供）：该提案的总体目标是开发具有临床转化潜力的小鼠β细胞团（BCM）的非侵入性全身成像。这些药物将用于研究各种小鼠模型中 I 型糖尿病的进展，以阐明该疾病的病因和进展。候选人 Greg Thurber 在了解显像剂的分布和药代动力学方面拥有丰富的经验，并将运用这些技能来设计新型药物并量化 BCM。用于测量 BCM 的显像剂的成功开发将为糖尿病研究领域做出重大贡献，极大地促进该疾病的诊断、进展和治疗干预。候选人的长期目标是开发新型成像剂来解决糖尿病研究中的重要生物学问题。这项工作将在哈佛/麻省总医院系统生物学中心在 Ralph Weissleder 博士的指导下进行。由于候选人在 T32 培训中与这位导师合作，他还聘请了糖尿病研究专家 Diane Mathis 博士和 Christophe Benoist 博士来提供额外的指导和专业知识。医学博士 Marcelo Di Carli 博士对深入了解临床翻译的支持也将包含在候选人的培训中。咨询委员会的这些成员将促进候选人的工作从主要导师手中过渡到作为独立糖尿病研究人员的成功职业生涯。该提案的具体目标是首先开发一种具有优化特性的 β 细胞成像剂，用于全身成像，然后在各种动物模型中进行体内成像。这项工作源于使用毒蜥外泌肽衍生物进行 β 细胞胰岛活体显微镜检查的初步研究。这些探针对于体内荧光成像具有最佳的药代动力学，但全身成像的额外限制，例如脱靶摄取和放射化学合成，使得这些探针并不理想。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，可以提高目标与背景的比率，从而提高检测的灵敏度。此外，模拟还表明了在炎症导致的可变递送情况下定量 BCM 所需的剂量和成像时间点。具体目标 1 将开发基于毒蜥外泌肽的新型探针，通过聚乙二醇化和/或特异性白蛋白结合肽降低血浆清除率，从而靶向 β 细胞。这是一种经过充分验证的延长血浆半衰期和减少肾脏摄取的方法，并且将利用广泛的体外和体内测试来确保充分的靶向性。具体目标 2 将利用新型四嗪和反式环辛烯化学物质快速放射性标记目标 1 中的新型探针，用于体内非侵入性成像。用于研究 1 型糖尿病的各种新型动物模型将使用新型探针进行成像，以测试成像信号对并发炎症的不同 BCM 的敏感性。如果成功，这些试剂将允许对任何疾病动物模型进行 BCM 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，全身成像使这些药物能够临床转化为监测患者的 BCM。公共健康相关性：该项目旨在创造用于监测 I 型糖尿病进展的新型显像剂。如果成功，这些药物将能够更早地诊断疾病，从而更有可能进行治愈性治疗，允许治疗监测，并为确定新疗法的有效性提供更好的工具。