Whole Body Imaging of Beta Cell Mass in Diabetes

描述（由申请人提供）：该提案的主要目标是开发具有临床转化潜力的小鼠β细胞团（β细胞团）的非侵入性全身成像。这些药物将用于在各种小鼠模型中研究I型糖尿病的进展，以阐明疾病的病因和进展。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，并将运用这些技能设计新型药物并量化药物。用于测量糖尿病的成像剂的成功开发将对糖尿病研究领域做出实质性贡献，极大地促进疾病的诊断、进展和治疗干预。候选人的长期目标是开发新型显像剂，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/MGH系统生物学中心进行，由Ralph Weissleder博士指导。由于候选人曾与这位导师一起进行T32培训，他还邀请了糖尿病研究专家Diane马西斯博士和Christophe Benoist博士进行额外的指导和专业知识。Marcelo Di Carli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的糖尿病研究人员发展成功的职业生涯。该提案的具体目的是首先开发具有优化的全身成像特性的β细胞成像剂，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衍生物进行β细胞胰岛活体显微镜检查的初步研究。这些探针具有用于体内荧光成像的最佳药代动力学，但是用于全身成像的额外约束，例如脱靶摄取和放射化学合成，使得这些探针不理想。广泛的药代动力学模拟表明，通过延长血浆半衰期和降低剂量，可以改善靶与背景的比率，提高检测的灵敏度。此外，模拟表明在由于炎症引起的可变递送的背景下定量TdR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，用于通过PEG化和/或特异性白蛋白结合肽降低血浆清除率来靶向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，将利用广泛的体外和体内试验来确保充分的靶向。特定目标2将利用新的四嗪和反式环辛烯化学来快速放射性标记来自目标1的新探针，用于体内非侵入性成像。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变化的灵敏度。如果成功的话，这些药物将允许对任何疾病动物模型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，全身成像使得这些药剂能够用于监测患者的呼吸道疾病的可能临床转化。

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.