Noninvasive Assessment of Pancreatic Beta-Cell Mass

胰腺 β 细胞质量的无创评估

• 批准号: 8538959
• 负责人: Orhan Kemal Oz
• 金额: $ 33.65万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538959
• 关键词: Acids; Atherogenic Diet; Behavior; Beta Cell; Binding; Biologic Characteristic; Biological; Biological Assay; Cell Line; Chelating Agents; Clinical; Clinical assessments; Complex; Contrast Media; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease; Educational workshop; Epidemic; Evaluation; Family suidae; Future; Genetic; Goals; Gold; Harvest; Healthcare; High Pressure Liquid Chromatography; Human; Image; Imaging Device; Imaging Techniques; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans Transplantation; Isotopes; Knowledge; Label; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Methods; Miniature Swine; Mission; Modeling; Monitor; Mus; National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Pancreas; Pathogenesis; Pathologic; Pathology; Patients; Physiological; Plant Roots; Population; Positron; Positron-Emission Tomography; Procedures; Property; Protocols documentation; Public Health; Radiometry; Rattus; Reproducibility; Research; Risk; Rodent; Rodent Model; Sensitivity and Specificity; Specificity; Staging; Structure of beta Cell of islet; Techniques; Testing; Time; Toxic effect; Tracer; Translating; Translations; Transplantation; Variant; analog; base; burden of illness; clinical practice; clinically relevant; diabetes management; diabetic; dihydrotetrabenazine; fasting glucose; glucagon-like peptide; glucagon-like peptide 1; imaging modality; imaging probe; improved; in vivo; insulinoma; islet; mouse model; novel; patient population; radiochemical; radiotracer; receptor; receptor density; research clinical testing; scaffold; success; tool; triazacyclononane; uptake

DESCRIPTION (provided by applicant): There is currently no non-invasive method to quantify beta-cell mass in humans. Continued existence of this gap represents an important problem because it potentially limits health care of patients with diabetes, with pancreas transplants, and leaves in place an unmet need for an imaging tool not only for mechanistic studies which evaluate the pathogenesis of this disease, but also as an outcome tool for new pharmacologic interventions. The long-term goal is to develop imaging methods, based on novel probes, for non-invasive assessment of beta cell mass (BCM) and function. Within the pancreas the glucagon-like peptide-1 receptor (GLP-1R) is uniquely expressed in the islets. The objective in this application is to develop and test a novel class of radiotracers for positron emission tomography (PET) imaging of beta cell mass based on analogues of GLP-1. The central hypothesis is GLP-1 based PET probes can be used to monitor BCM change with clinically acceptable specificity, accuracy, and reproducibility. This hypothesis has been formulated on the basis of preliminary data derived from successful development of a bicyclic GLP-1 analog for beta cell specific imaging in mice. The rationale for the proposed research is that development of these probes and the attendant imaging method has the potential to translate into better health care of patients with diabetes, currently 8% of the US population, and patients with pancreas or islet cell transplants, and insulinomas. Guided by strong preliminary data, the hypothesis will be tested by pursuing three specific aims: Aim 1: To synthesize, characterize, and evaluate NOTA-(EM2198)n. Multimers of EM2198 on a novel class of bifunctional chelator scaffolds together with the PET isotope, 68Ga will enhance the sensitivity and specificity of imaging. The scaffold precursors and EM2198 conjugates will be synthesized by existing methods. The biological behavior will be evaluated using cell lines, freshly isolated rat/pig islets, and mouse models; Aim 2: To determine the accuracy and reproducibility of PET-CT imaging of BCM in a clinically relevant model, namely Ossabaw minipigs. Mini-pigs have genetic, anatomical, and physiological similarities to humans. The Ossabaw miniature pigs develop type 2 diabetes when placed on an atherogenic diet. PET measures of 68Ga-NOTA-EM2198 uptake will be correlated with the gold standard of pathology assay of porcine pancreas. Aim 3: To longitudinally monitor the dynamic BCM change in T2D Ossabaw swine and assess the potential toxic effect of the longitudinal imaging procedure. Serial PET-CT imaging will be performed on lean and diabetic Ossabaw swine before the onset and during the progression of T2D. Imaging and clinical outcomes will be correlated. The potential risk of this longitudinal imaging technique and radiation dosimetry will be determined. Upon the successful completion of this project, we expect to have a safe imaging technique available for further clinical evaluation.

描述（由申请人提供）：目前尚无非侵入性方法来定量人体β细胞质量。这一差距的持续存在代表了一个重要的问题，因为它可能限制了糖尿病患者的医疗保健，胰腺移植，并留下了一个未满足的需要，成像工具不仅用于机制研究，评估这种疾病的发病机制，而且作为一个结果工具，新的药理学干预。长期目标是开发基于新型探针的成像方法，用于非侵入性评估β细胞质量（β细胞）和功能。在胰腺内，胰高血糖素样肽-1受体（GLP-1 R）仅在胰岛中表达。本申请的目的是开发和测试一类新型放射性示踪剂，用于基于GLP-1类似物的β细胞团的正电子发射断层扫描（PET）成像。中心假设是基于GLP-1的PET探针可用于监测具有临床可接受的特异性、准确性和再现性的血小板变化。这一假设是基于成功开发用于小鼠β细胞特异性成像的双环GLP-1类似物的初步数据制定的。拟议研究的基本原理是，这些探针和伴随的成像方法的开发有可能转化为糖尿病患者（目前占美国人口的8%）以及胰腺或胰岛细胞移植和胰岛素瘤患者的更好医疗保健。在强有力的初步数据的指导下，该假设将通过追求三个具体目标进行测试：目标1：合成，表征和评估NOTA-（EM 2198）n。EM 2198在新型双功能螯合剂支架上的多聚体与PET同位素68 Ga一起将增强成像的灵敏度和特异性。支架前体和EM 2198缀合物将通过现有方法合成。将使用细胞系、新鲜分离的大鼠/猪胰岛和小鼠模型评价生物学行为;目的2：确定临床相关模型（即Ossabaw小型猪）中胰岛PET-CT成像的准确性和重现性。迷你猪与人类在遗传、解剖和生理上都有相似之处。Ossabaw小型猪在食用致动脉粥样硬化饮食时会患上2型糖尿病。68 Ga-NOTA-EM 2198摄取的PET测量将与猪胰腺病理学测定的金标准相关联。目标三：纵向监测T2 D Ossabaw猪的动态MRI变化，并评估纵向成像程序的潜在毒性效应。将在T2 D发作前和进展期间对瘦型和糖尿病Ossabaw猪进行连续PET-CT成像。影像学和临床结局将相互关联。将确定这种纵向成像技术和辐射剂量测定的潜在风险。在成功完成该项目后，我们希望有一个安全的成像技术可用于进一步的临床评价。