Development and characterization of ultra-stable insulin analogs for novel therapeutic use
Development and characterization of ultra-stable insulin analogs for novel therapeutic use
批准号:
9259099
负责人:
Nischay Kiran Rege
金额:
$4.68万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-12-01 至 2020-11-30
关键词:
AdherenceAffinityAmidesAmino Acid SequenceAmyloidAnabolismAnimal ModelBiochemistryBiocompatible MaterialsBiologicalBiological AssayBiomedical EngineeringBlood Glucose Self-MonitoringBuffersCellsCharacteristicsChemicalsCircular DichroismClinicalCold ChainsCollaborationsCommunitiesComplementComplexConsultCystineDevelopmentDevicesDiabetes MellitusDiseaseDisulfidesDoctor of MedicineDoctor of PhilosophyDoseDrug Delivery SystemsDrug KineticsEatingEngineeringEnzyme-Linked Immunosorbent AssayEvaluationExhibitsFDA approvedFormulationFrequenciesFurunclesFutureGlycolatesGray unit of radiation doseHealthHealthcareHeatingHigh temperature of physical objectHormone ReceptorHormonesHourHypoglycemiaImplantIn VitroInjection Site ReactionInjection of therapeutic agentInstitutesInsulinInsulin ReceptorInsulin-Dependent Diabetes MellitusInsulin-Like-Growth Factor I ReceptorIntravenousIntravenous BolusIsoelectric PointLaboratory StudyLectinLettersLifeLong-Acting InsulinLongevityMassachusettsMeasuresMedicineMentorshipMethodsModelingModificationNMR SpectroscopyNatureNeedlesNon-Insulin-Dependent Diabetes MellitusOralOutcomeParentsPatientsPeptide Sequence DeterminationPharmacodynamicsPichiaPilot ProjectsPolymersPositioning AttributePredispositionPrevalencePropertyProtein EngineeringProtein IsoformsProteinsProtonsPublic HealthRattusRegimenReplacement TherapyRiskSafetyScienceScientistStreptozocinStructureStudentsSuspension substanceSuspensionsSystemTechnologyTemperatureTestingTherapeutic UsesTimeTrainingUnited StatesX-Ray CrystallographyYeastsanalogbasal insulinbasecareerclinical caredesigndiabeticglucose monitorglycemic controlhealth disparityimprovedimproved outcomeinterestmalemanufacturing processmeltingmid-career facultymolecular dynamicsnovelnovel therapeuticspandemic diseasepatient subsetspeptide hormonepotency testingprofessorresiliencesubcutaneousthermal stresstype I and type II diabetes
中文摘要
糖尿病是一项重大的公共卫生负担。无论是在美国还是在世界各地,
英文摘要
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.
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