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In vitro bioreactor system for platelet formation

用于血小板形成的体外生物反应器系统

基本信息

批准号：
9309214
负责人：
ALESSANDRA BALDUINI
金额：
$ 35.46万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309214
关键词：
Acute Address Adult Adverse effects Affect Behavior Biochemical Biocompatible Materials Biology Bioreactors Blood Blood Platelets Blood Vessels Bone Marrow Cells Clinical Collaborations Collagen Collagen Type IV Collection Communities Data Development Devices Diagnosis Diagnostic Dimensions Disease Engineering Environment Fibrinogen Fibronectins Future Goals Grant Health Human Human Pathology In Vitro Inherited Injection of therapeutic agent Japan Label Life Megakaryocytes Megakaryocytopoieses Modeling Modification Myeloproliferative disease Nutrient Outcome Outcome Study Oxygen Palliative Care Paris, France Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacotherapy Physiological Platelet Activation Platelet Count measurement Platelet Transfusion Porifera Preclinical Drug Evaluation Process Production Proteins Protocols documentation Recombinant Proteins Recovery Research Personnel Safety Science Signal Transduction Silk Source Stream System Tail Technology Testing Therapeutic Thrombocytopenia Thrombopoietin Thrombosis Tissue Model Transfusion Umbilical Cord Blood Uncertainty Vascular Endothelium Veins Work base bone engineering clinical application clinically relevant design drug candidate drug efficacy extracellular genetic manipulation improved in vivo induced pluripotent stem cell inhibitor/antagonist insight mimetics mouse model novel novel therapeutics peripheral blood predictive tools progenitor programs public health relevance recombinant human thrombopoietin research study response screening shear stress success targeted treatment therapeutic development tool two-dimensional

项目摘要

Summary In various human pathologies there are countless alterations in platelet production or function. Yet many of these pathogenesis and the required targeted therapies remain unknown, resulting in palliative treatments. In vivo, megakaryocytes associate with the bone marrow microvasculature where they extend proplatelets that protrude through the vascular endothelium into the lumen and release platelets into the blood stream. The scientific and clinical communities are actively searching for new modes to generate functional platelets ex vivo to address clinical needs as well as for insight into fundamental studies of mechanisms. We hypothesize that engineering a 3D bone marrow mimic, as demonstrated in our current grant, will propel mechanistic understanding of platelet shedding and determine future protocols for therapeutic inquiry. To test our hypothesis, in Aim 1 we will utilize non-thrombogenic silk protein biomaterial in a modified ex vivo three dimensional (3D) tissue model of the bone marrow to study platelet release from megakaryocytes derived from human induced pluripotent stem cells (hiPSCs); to compare with the results in the current grant using megakaryocytes from umbilical cord blood progenitors. In Aim 2 we will focus on the use of the bioreactor systems to study the effects of thrombopoietin mimetics on human megakaryocytes derived from patients affected by inherited thrombocytopenias and healthy controls. In Aim 3 we will conduct studies to assess the functionality of the platelets released in the bioreactor systems in vitro and in vivo. The outcome of these studies is expected to be unprecedented insight into mechanisms that control platelet formation. These insights will build on our ability to generate functional human platelets ex vivo but with significant improvements in cell sources, disease insight and functional assessments in this renewal proposal. The development of a unified solution based on the proposed science and technologies will clarify the impact of thrombopoietin mimetics on human megakaryocyte behaviour in terms of activation of intracellular signaling, differentiation, interaction with the extracellular environment and platelet production, all with major implications for human health. Importantly, the successful outcome of this project will provide researchers with new specialized tools for predicting the efficacy and safety of new drugs to address megakaryocyte- related diseases. In addition, the results will provide an important next step towards clinically relevant sources and supplies of functional human platelets for patient treatments.

总结