Noninvasive Assessment of Pancreatic Beta-Cell Mass

胰腺 β 细胞质量的无创评估

• 批准号: 8150302
• 负责人: Orhan Kemal Oz
• 金额: $ 40.81万
• 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/8150302
• 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the development of novel imaging probes to noninvasively monitor pancreatic beta cell mass (BCM) is ultimately expected to impact health care of patients with diabetes, a global epidemic. Thus, the proposed research is relevant to the part of NIH's mission that pertains to seeking fundamental knowledge that will reduce the burdens of illness.

描述（由申请人提供）：目前没有非侵入性方法来量化人体内的β细胞质量。这种差距的持续存在是一个重要的问题，因为它可能限制糖尿病患者和胰腺移植患者的医疗保健，并且对成像工具的需求未得到满足，不仅用于评估该疾病发病机制的机制研究，而且还作为新的药物干预的结果工具。长期目标是开发基于新型探针的成像方法，用于无创评估β细胞质量（BCM）和功能。胰高血糖素样肽-1受体（GLP-1R）在胰岛中唯一表达。本应用的目的是开发和测试一种新型放射性示踪剂，用于基于GLP-1类似物的β细胞质量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BCM变化，具有临床可接受的特异性，准确性和可重复性。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类似物的初步数据而制定的。提出这项研究的基本原理是，这些探针和随之而来的成像方法的发展有可能为糖尿病患者（目前占美国人口的8%）、胰腺或胰岛细胞移植患者和胰岛素瘤患者提供更好的医疗保健。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来验证：目标1：合成，表征和评估NOTA-(EM2198)n。新型双功能螯合剂支架上的EM2198多聚体与PET同位素68Ga将增强成像的灵敏度和特异性。支架前体和EM2198偶联物将通过现有方法合成。生物学行为将通过细胞系、新分离的大鼠/猪胰岛和小鼠模型进行评估；目的2：确定PET-CT成像在临床相关模型，即Ossabaw迷你猪中BCM的准确性和可重复性。迷你猪在遗传、解剖和生理上都与人类相似。Ossabaw迷你猪在食用致动脉粥样硬化的食物时会患上2型糖尿病。PET测定的68Ga-NOTA-EM2198摄取量与猪胰腺病理检测的金标准相关。目的3：纵向监测T2D奥沙巴猪BCM的动态变化，并评估纵向成像程序的潜在毒性作用。瘦猪和糖尿病奥沙巴猪将在T2D发病前和发展过程中进行连续PET-CT成像。影像学和临床结果将相互关联。这种纵向成像技术和辐射剂量学的潜在风险将被确定。在这个项目成功完成后，我们期望有一种安全的成像技术可用于进一步的临床评估。