Engineering Receptors to Control Platelet Activation and Therapeutic Release

工程受体来控制血小板激活和治疗释放

基本信息

批准号：
10607886
负责人：
Shwan B Javdan
金额：
$ 2.65万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10607886
关键词：
Alkaline Phosphatase Area Automobile Driving Behavior Control Blood Cells Blood Platelets Brain CRISPR/Cas technology Cell Therapy Cells Clinical Coagulation Process Cytoplasm Cytoplasmic Granules Derivation procedure Development Devices Directed Molecular Evolution Disease Dose Drug Delivery Systems Engineering Ensure Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genetic Genome engineering Goals Heart Diseases Hematopoiesis Hemostatic function Human In Vitro Inflammation Link Location Lymphoma Megakaryocytes Methods Multiple Myeloma Mus Pathway interactions Patients Pharmaceutical Preparations Physiological Processes Platelet Activation Pluripotent Stem Cells Production Proteinase-Activated Receptors Proteins Receptor Activation Receptor Gene Research Role Scientist Shapes Signal Pathway System Testing Therapeutic Thrombin Training Work angiogenesis career cell type clinical translation controlled release delivery vehicle design designer receptors exclusively activated by designer drugs embryonic stem cell empowerment in vivo induced pluripotent stem cell mouse genetics mouse model non-Native novel novel strategies pharmacologic platelet function precursor cell receptor receptor binding receptor function small molecule spatiotemporal success synthetic biology therapeutic protein tool translational therapeutics wound healing

项目摘要

PROJECT SUMMARY: While the use of living cells as therapeutic delivery vehicles has become a prominent area of focus in recent years, challenges remain in achieving clinical translation due to limitations on available therapeutic loading methods as well as lack of controlled therapeutic release mechanisms. Platelets offer a unique delivery platform as they are anucleate cells naturally loaded with proteins from their megakaryocyte precursor cells, and release their intracellular contents once activated. We have shown that megakaryocytes can be loaded with proteins that are packaged into platelets, creating engineered platelets that function as novel delivery devices. However, a key challenge remains that the native activation pathway of platelets may cause the activation and subsequent release of therapeutic payloads in undesired locations. Thus, there is a critical need for a controllable activation trigger in engineered platelets, specifically, one that is orthogonal to the native activation pathway. Here, we engineered a set of novel platelet receptors that can be activated only by a pharmacologically inert small molecule drug to enable the controlled release of the therapeutic payload carried by engineered platelets.

项目摘要：虽然将活细胞用作治疗递送车辆已成为最近的重点领域多年来，由于可用的治疗负荷限制，在实现临床翻译方面仍然存在挑战方法以及缺乏受控的治疗释放机制。血小板提供独特的送货平台因为它们是核酸菌细胞，自然地从其巨核细胞前体细胞中加载蛋白质，并释放它们的细胞内含量曾经激活。我们已经证明，巨核细胞可以装有蛋白质被包装到血小板中，创建具有新型交付设备的工程血小板。但是，主要挑战仍然是，血小板的天然激活途径可能导致激活和随后的激活在不希望的位置释放治疗有效载荷。因此，迫切需要可控的激活触发工程的血小板，特别是与天然激活途径正交的触发。在这里，我们设计了一组新型血小板受体分子药物可以使工程血小板携带的治疗有效载荷的受控释放。