Development and characterization of ultra-stable insulin analogs for novel therapeutic use

用于新型治疗用途的超稳定胰岛素类似物的开发和表征

基本信息

批准号：
9259099
负责人：
Nischay Kiran Rege
金额：
$ 4.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259099
关键词：
Adherence Affinity Amides Amino Acid Sequence Amyloid Anabolism Animal Model Biochemistry Biocompatible Materials Biological Biological Assay Biomedical Engineering Blood Glucose Self-Monitoring Buffers Cells Characteristics Chemicals Circular Dichroism Clinical Cold Chains Collaborations Communities Complement Complex Consult Cystine Development Devices Diabetes Mellitus Disease Disulfides Doctor of Medicine Doctor of Philosophy Dose Drug Delivery Systems Drug Kinetics Eating Engineering Enzyme-Linked Immunosorbent Assay Evaluation Exhibits FDA approved Formulation Frequencies Furuncles Future Glycolates Gray unit of radiation dose Health Healthcare Heating High temperature of physical object Hormone Receptor Hormones Hour Hypoglycemia Implant In Vitro Injection Site Reaction Injection of therapeutic agent Institutes Insulin Insulin Receptor Insulin-Dependent Diabetes Mellitus Insulin-Like-Growth Factor I Receptor Intravenous Intravenous Bolus Isoelectric Point Laboratory Study Lectin Letters Life Long-Acting Insulin Longevity Massachusetts Measures Medicine Mentorship Methods Modeling Modification NMR Spectroscopy Nature Needles Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Parents Patients Peptide Sequence Determination Pharmacodynamics Pichia Pilot Projects Polymers Positioning Attribute Predisposition Prevalence Property Protein Engineering Protein Isoforms Proteins Protons Public Health Rattus Regimen Replacement Therapy Risk Safety Science Scientist Streptozocin Structure Students Suspension substance Suspensions System Technology Temperature Testing Therapeutic Uses Time Training United States X-Ray Crystallography Yeasts analog basal insulin base career clinical care design diabetic glucose monitor glycemic control health disparity improved improved outcome interest male manufacturing process melting mid-career faculty molecular dynamics novel novel therapeutics pandemic disease patient subsets peptide hormone potency testing professor resilience subcutaneous thermal stress type I and type II diabetes

项目摘要

Diabetes mellitus poses a major public-health burden. Both in the United States and throughout the world, progressive increases have been observed in the prevalence of both Type 1 diabetes mellitus (T1DM) and Type 2 diabetes (T2DM). This application focuses on the development of thermodynamically stable insulin analogs that may be applied to novel drug-delivery systems. The applicant is an MSTP student who seeks training in biochemistry toward a future career that integrates clinical care with the development of novel therapeutics and devices. Clinical insulin regimens must compensate for the loss of regulated secretion by careful dosing coordinated with the patient's food intake, level of activity, and results of serial glucose monitoring. Adherence to such regimens requires self-injections several times a day. Such delivery methods not only cause discomfort for the patient, but they are also difficult to maintain in terms of timing and accurate administration of doses. The safety and efficacy of current regimens may be enhanced through the development of alternative mechanisms for insulin administration. Insulin's nature as a peptide hormone that is susceptible to chemical and temperature-induced degradation is a major barrier for its implementation in novel delivery systems. This application describes the combination of two previously characterized stabilizing modifications of the insulin hormone that will be used to create heat-stable insulin analogs that can be fabricated into PLGA- polymeric matrices and retain their biological activity. These insulin-infused polymers will be developed into microneedle implants that will serve as basal insulin delivery systems. These implants will reduce the frequency of self-injection while delivering safe, consistent, and continuous doses of insulin. Because of the interdisciplinary nature of the proposed studies, laboratory mentorship by the primary Thesis Advisor (M. Weiss, M.D., Ph.D.; Professor of Biochemistry, Biomedical Engineering & Medicine) will be complemented by a master clinician (diabetologist F. Ismail-Beigi, Professor of Medicine), an X-ray crystallography expert (V. Yee; Associate Professor of Biochemistry), and materials-scientist specializing in macromolecular sciences (J. Pokorski; Professor of Macromolecular Sciences). Additionally, consulting advisors D. Anderson and R. Langer, protein engineers at the Massachusetts Institute of Technology, will provide additional guidance on the development of the project.

糖尿病会带来重大的公共卫生负担。在美国和世界各地，两种型糖尿病（T1DM）和 2型糖尿病（T2DM）。该应用的重点是热力学稳定胰岛素的发展可以应用于新型药物递送系统的类似物。申请人是一名MSTP学生，寻求生物化学培训朝着未来的职业，将临床护理与新颖的发展融合治疗和设备。临床胰岛素方案必须通过仔细给药协调来补偿受调节分泌的损失随着患者的食物摄入量，活动水平和连续葡萄糖监测的结果。坚持这样方案每天需要几次自我注射。这种交付方法不仅会引起不适患者，但在时间安排和准确给药剂量方面也很难维持。这通过开发替代机制可以增强当前方案的安全性和功效用于胰岛素给药。胰岛素的本质是易于化学和化学的肽激素温度引起的降解是其在新型输送系统中实施的主要障碍。该应用描述了两个先前表征的稳定修饰的组合胰岛素激素将用于产生热稳定的胰岛素类似物，可用于PLGA- 聚合矩阵并保留其生物学活性。这些注入胰岛素的聚合物将被发展为将作为基础胰岛素输送系统的微针植入物。这些植入物将减少自我注射的频率，同时提供安全，一致和连续的胰岛素剂量。由于拟议研究的跨学科性质，主要论文实验室指导顾问（M. Weiss，医学博士，博士；生物医学工程与医学生物化学教授）将是 X射线晶体学专家（V. Yee；生物化学副教授）和专业的材料科学家大分子科学（J. Pokorski；大分子科学教授）。另外，咨询马萨诸塞州理工学院的蛋白质工程师Advisors D. Anderson和R. Langer将提供有关项目开发的其他指导。