New Mechanistic Insights & Therapeutic Applications of Megakaryocytes/Platelets

新的机制见解

• 批准号: 10616531
• 负责人: Mortimer Poncz
• 金额: $ 105.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616531
• 关键词: Affect; Antibodies; Area; Award; Beds; Benign; Biology; Blood Platelet Disorders; Blood Platelets; Blood coagulation; Bone Marrow; Career Mobility; Caring; Cells; Complementary DNA; Cytoplasmic Granules; Defect; Disease; Factor VIII; Genes; Grant; Hematology; Hemophilia A; Hemorrhage; In Situ; In Vitro; Inherited; Integrins; Intervention; Lung; Medical; Megakaryocytes; Megakaryocytopoieses; Modeling; Molecular; National Heart, Lung, and Blood Institute; Nature; PF4 Gene; PPBP gene; Paris, France; Patients; Physiological; Platelet Transfusion; Process; Proteins; RUNX1 gene; Research Personnel; Risk; Role; Sepsis; Sickle Cell Anemia; Site; Syndrome; Testing; Therapeutic; Thrombasthenia; Thrombocytopenia; Thrombopoiesis; Time; Urokinase; Variant; capillary bed; chemokine; clinical application; extracellular; heparin-induced thrombocytopenia; improved outcome; induced pluripotent stem cell; inhibitor; insight; interest; leukemic transformation; mouse model; neutrophil; novel; novel therapeutics; polyanion; targeted treatment; thromboinflammation; transcription factor; vascular injury

ABSTRACT This is an application by Mortimer Poncz, MD, for an NHLBI-supported R35 Outstanding Investigator Award (OIA). Dr. Poncz has made pioneering contributions to the field of platelet (Plt) biology. He isolated and charac- terized the first cDNAs and genes for the Plt proteins (integrin chains, aIIb and b3, and the chemokines, platelet factor 4 (PF4) and b-thromboglobulin). He characterized the first molecular defects in an inherited Plt disorder, Glanzmann thrombasthenia (GT). For over 30 years, Dr. Poncz has made insightful contributions to move the Plt field forward. He helped advance our understanding of megakaryopoiesis, defining many of the transcriptional factors (TFs) fundamental to that process and their role in inherited Plt disorders. He pioneered the use of induced pluripotent stem cells (iPSCs) to study megakaryocyte (Meg) biology and demonstrated the first strategy for genetically correcting the defect in GT and in Paris-Trousseau syndrome. Dr. Poncz proposes to pursue new insights into the molecular basis of the thrombocytopenia observed in RUNX1 haploinsufficiency, and how this intervention might decrease the risk of leukemic transformation in affected patients. This interest in megakaryopoiesis also lead to Dr. Poncz’s contribution to understanding where Plts are released, showing that infused Megs release Plts in the lungs. The resulting Plts are much more physiologic than any ex vivo-generated Plts released from in vitro-grown Megs to date. These studies supported a potential pulmonary site for a portion of thrombopoiesis with subsequent studies by others providing in situ-support for this model. Dr. Poncz now shows that the lung microcapillary bed is unique in being able to release Plts. Proposed studies will further our understanding of what makes the pulmonary bed unique for thrombopoiesis, and such insights may have clinical application in Plt transfusions. Dr. Poncz also proposed that Plts could store ectopic proteins in a granules, releasing them in a targeted, potent fashion at sites of vascular injury. He proposes advancing the use of Plt-targeted therapeutics by a novel new mechanism for loading such proteins into Plts to treat hemophilia A patients with inhibitors with Factor VIII variants and for use as a thromboprophylaxis agent with urokinase variants. Dr. Poncz has also advanced our understanding of the molecular basis of prothrombotic heparin-induced thrombocytopenia (HIT). His HIT-like antibody KKO and murine model for HIT are widely used in the field and both were used in his recent advances in understanding the role of neutrophil extracellular traps (NETs) in HIT. He now proposes that polyanions like NETs underlie the prothrombotic nature of HIT, and will test this in this R35. Moreover, he believes that these new insights have implications in the care of other thromboinflammatory diseases where NETs have an important role, and proposes use of PF4 and Fc-modified KKO in the treatment of sepsis and sickle cell disease. Support from this R35 OIA mechanism will also provide Dr. Poncz with the time to pursue his other passion of advancing the career of mentees in areas related to benign hematology.

摘要 这是一个应用程序由莫蒂默庞茨，医学博士，为NHLBI支持的R35杰出研究者奖 （内审办）。Poncz博士在血小板（Plt）生物学领域做出了开创性的贡献。他孤立和charac- 鉴定了Plt蛋白的第一个cDNA和基因（整联蛋白链，aIIb和b3，以及趋化因子， 血小板因子4（PF 4）和b-血小板球蛋白）。他描述了遗传性血小板减少性紫癜的第一个分子缺陷， 血小板无力症（GT）。30多年来，Poncz博士为以下方面做出了深刻的贡献： 向前移动Plt字段。他帮助推进了我们对巨核细胞生成的理解，定义了许多 转录因子（TF）的基础上，这一进程和他们的作用，遗传性血小板异常。他 率先使用诱导多能干细胞（iPSC）研究巨核细胞（Meg）生物学， 证明了遗传纠正GT和Paris-Trousseau综合征缺陷的第一个策略。 博士Poncz建议对血小板减少症的分子基础进行新的研究， RUNX 1单倍不足，以及这种干预如何降低白血病转化的风险。 受影响的患者。这种对巨核细胞生成的兴趣也导致了Poncz博士对理解 其中Plts被释放，表明输注的Meg在肺中释放Plts。由此产生的Plts是多 比迄今为止从体外生长的Megs释放的任何离体产生的Plt更具生理性。这些研究 其他人的后续研究支持了部分血栓形成的潜在肺部部位 为这一模式提供现场支持。Poncz博士现在表明，肺微毛细血管床是独特的， 能够释放Plts。拟议的研究将进一步我们的理解是什么使肺床 独特的血小板生成，这样的见解可能在血小板输注的临床应用。庞茨博士也 提出Plts可以将异位蛋白储存在颗粒中，以靶向的，有效的方式释放它们， 血管损伤部位。他建议通过一种新的方法来推进Plt靶向治疗的使用。 将这些蛋白质装载到Plt中以用因子VIII的抑制剂治疗血友病A患者的机制 变体，并用作具有尿激酶变体的血栓预防剂。庞茨博士还提出了我们的 了解血栓前肝素诱导的血小板减少症（HIT）的分子基础。他 HIT样抗体KKO和HIT的鼠模型在该领域中被广泛使用，并且两者都在他最近的研究中使用。 了解中性粒细胞胞外陷阱（NET）在HIT中的作用的进展。他现在提出， NET等聚阴离子是HIT促血栓形成性质的基础，并将在R35中测试这一点。而且他 相信这些新的见解对其他血栓炎性疾病的治疗有影响， NET具有重要的作用，并提出使用PF 4和Fc修饰的KKO治疗脓毒症 和镰状细胞病。来自这一R35 OIA机制的支持也将为Poncz博士提供时间， 追求他的另一个激情，在良性血液学相关领域推动学员的职业生涯。