Whole Body Imaging of Beta Cell Mass in Diabetes

糖尿病β细胞团的全身成像

• 批准号: 8332881
• 负责人: Greg Thurber
• 金额: $ 16.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332881
• 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; 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

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.

描述（由申请人提供）：该提案的广泛目标是在小鼠中开发对β细胞量（BCM）的无创全身成像，具有临床翻译的潜力。这些药物将用于研究多种小鼠模型中I型糖尿病的进展，以阐明疾病的病因和进展。候选人格雷格·瑟伯（Greg Thurber）在理解成像剂的分布和药代动力学方面拥有丰富的经验，并将应用这些技能来设计新颖的代理和量化BCM。用于测量BCM的成像剂的成功开发将为糖尿病研究领域做出重大贡献，从而极大地促进了该疾病的诊断，进展和治疗干预措施。候选人的长期目标是开发新颖的成像剂，以解决糖尿病研究中重要的生物学问题。这项工作将在Ralph Weissleder MD博士的指导下在哈佛/MGH系统生物学中心进行。由于候选人与这位导师进行T32培训合作，因此他还提出了戴安娜·马蒂斯（Diane Mathis Phd）博士和克里斯托夫·贝诺斯特（Christophe Benoist）博士MD博士学位，这都是糖尿病研究专家，以提供额外的指导和专业知识。 Marcelo di Carli博士医学博士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的过渡，以发展独立的糖尿病研究人员的成功职业。该提案的具体目的首先开发出具有优化特性的Beta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。这项工作源于使用外脱素衍生物进行β细胞胰岛插入式显微镜的初步研究。这些探针具有用于体内荧光成像的最佳药代动力学，但是全身成像的其他约束（例如关闭靶标摄取和放射化学合成）使这些探针非理想化。广泛的药代动力学模拟表明，通过扩展血浆半寿命并减少剂量，可以提高目标与背景比率，从而提高检测的敏感性。此外，模拟表明在炎症引起的可变递送情况下定量BCM所需的剂量和成像时间点。特定的目标1将通过降低血浆和/或特定的白蛋白结合肽来基于β细胞靶向的脱发素肽来开发新的探针。这是一种良好验证的方法，用于扩展血浆半衰期并减少肾脏摄取，并且将利用广泛的体外和体内测试来确保足够的靶向靶向。特定的目标2将利用新型的四嗪和反循环八烯化学来快速放射性标记，从AIM 1中的新型探针进行体内非侵入性成像。用于研究1型糖尿病的各种新型动物模型将与新型探针成像，以测试成像信号对与同时炎症变化BCM的敏感性。如果成功，这些药物将允许对任何疾病动物模型进行BCM的纵向非侵入性成像，并可用于监测进展和测量治疗干预。此外，整个身体成像还可以使这些药物的临床翻译可能用于监测患者的BCM。