The mechanism and clinical implications of the negative paracrine effect of PF4

PF4负性旁分泌作用的机制和临床意义

• 批准号: 7447984
• 负责人: MICHELE P LAMBERT
• 金额: $ 16.09万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447984
• 关键词: Acute Lymphocytic Leukemia; Adult; Affect; Age; American; Apoptosis; Appearance; Award; Blood; Blood Platelets; Blood donor; Cancer Patient; Caring; Cells; Child; Childhood; Chronic; Clinical; Clinical Research; Cytolysis; Cytoplasmic Granules; Cytotoxic Chemotherapy; Data; Defect; Development; Disease; Disease remission; Dose; Dysmyelopoietic Syndromes; Endothelial Cells; Ethnic Origin; Follow-Up Studies; Funding; Future; Hematologist; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Hemostatic function; Human; Immune; In Vitro; Individual; Injury; Institution; LDL-Receptor Related Protein 1; Lead; Length; Lipoprotein Receptor; Marrow; Medical History; Megakaryocytes; Megakaryocytopoieses; Mentors; Modeling; Molecular; Molecular Biology; Mus; Numbers; Pathogenesis; Patients; Physicians; Pilot Projects; Platelet Activation; Platelet Count measurement; Platelet Factor 4; Platelet Transfusion; Play; Population; Postdoctoral Fellow; Process; Proteins; Purpose; Purpura; Recovery; Red Cross; Regulation; Research; Research Personnel; Risk; Role; Sampling; Scientist; Severities; Staging; Standards of Weights and Measures; Stem cells; Structure; Testing; Thrombocytopenia; Time; Training; Transfusion; Translating; Vascular Diseases; abstracting; base; career; chemokine; chemotherapy; clinical application; clinically relevant; cytokine; day; experience; in vivo; insight; interest; novel; novel therapeutics; paracrine; precursor cell; prevent; progenitor; programs; receptor; scavenger receptor; sex; size; sound; therapeutic target

DESCRIPTION (provided by applicant): Thrombocytopenia is a significant clinical problem post-chemotherapy and in patients with immune thrombocytopenia purpura and myelodysplastic syndrome, all of which are associated with intramedullary megakaryocyte apoptosis. Using murine models, I have demonstrated that platelet factor 4 (PF4), which is synthesized in developing megakaryocytes, is released from these cells and behaves as a negative paracrine, especially in clinical settings associate with intramedullary lysis of megakaryocytes. Further, in a murine model of chemotherapy-induced thrombocytopenia (CIT), strategies that block PF4 can ameliorate the thrombocytopenia. This application is to support a mentored research experience as I translate my murine studies to clinical application. These observations will be expanded in three specific aims. Specific Aim 1: Define the role of PF4 in megakaryopoiesis in human primary hematopoietic cells. I have found that PF4 may target a megakaryocyte precursor cell through the scavenger receptor LRP-1 in mice. I propose to define the specific megakaryocyte progenitor cell targeted in humans and demonstrate that these cells express LRP-1 and that PF4 affects human megakaryopoiesis through these receptors. These studies will provide important insight into the molecular biology of megakaryopoiesis and may in lead to novel therapeutic strategies to prevent thrombocytopenia in CIT and related clinical settings. Specific Aim 2: Define the distribution of PF4 in a normal pediatric population. Preliminary data using adult samples suggest that -10% of the human population has high platelet PF4 levels. I plan to confirm this result in a healthy population in whom platelet PF4 levels should reflect megakaryocyte PF4 levels as a prelude to studies in the following specific aim that will examine whether patients with high PF4 levels are at greater risk of significant CIT. Specific Aim 3: Clinical studies of the in vivo inhibition of megakaryopoiesis by PF4. I will analyze the relationship between platelet PF4 content and the duration and severity of thrombocytopenia in a common form of cancer where patients have a fairly uniform clinical course and in which a significant number of patients undergo remission. The broader impact of this research is a better understanding of megakaryopoiesis leading to novel therapies for thrombocytopenia in multiple clinical settings. Combined with my didactic training and structured mentoring in this application, I believe that the proposed research will provide novel new insights into the management of thrombocytopenia in a number of important settings and should enable me to establish myself as an independently funded pediatric hematologist with expertise in the care and management of the thrombocytopenias. (End of Abstract)

描述（由申请人提供）：血小板减少症是化疗后以及免疫性血小板减少性紫癜和骨髓增生异常综合征患者的一个重要临床问题，所有这些都与髓内巨核细胞凋亡有关。使用小鼠模型，我证明了在发育中的巨核细胞中合成的血小板因子 4 (PF4) 从这些细胞中释放出来，并表现为负性旁分泌，特别是在与巨核细胞髓内裂解相关的临床环境中。此外，在化疗引起的血小板减少症 (CIT) 的小鼠模型中，阻断 PF4 的策略可以改善血小板减少症。该应用程序旨在支持我将小鼠研究转化为临床应用时的指导研究经验。这些观察结果将在三个具体目标中得到扩展。具体目标 1：确定 PF4 在人类原代造血细胞巨核生成中的作用。我发现 PF4 可能通过小鼠体内的清道夫受体 LRP-1 靶向巨核细胞前体细胞。我建议定义针对人类的特定巨核祖细胞，并证明这些细胞表达 LRP-1，并且 PF4 通过这些受体影响人类巨核细胞生成。这些研究将为巨核细胞生成的分子生物学提供重要的见解，并可能带来预防 CIT 和相关临床环境中血小板减少症的新治疗策略。具体目标 2：确定 PF4 在正常儿科人群中的分布。使用成人样本的初步数据表明，-10% 的人群具有较高的血小板 PF4 水平。我计划在健康人群中确认这一结果，其中血小板 PF4 水平应反映巨核细胞 PF4 水平，作为以下具体目标研究的前奏，该目标将检查高 PF4 水平的患者是否面临更大的显着 CIT 风险。具体目标 3：PF4 体内巨核细胞生成抑制的临床研究。我将分析一种常见癌症中血小板 PF4 含量与血小板减少症的持续时间和严重程度之间的关系，这种癌症的患者具有相当一致的临床病程，并且大量患者获得缓解。这项研究的更广泛影响是更好地了解巨核细胞生成，从而在多种临床环境中开发出治疗血小板减少症的新疗法。结合我在本申请中的教学培训和结构化指导，我相信拟议的研究将为许多重要环境中血小板减少症的管理提供新颖的见解，并使我能够成为一名独立资助的儿科血液学家，具有以下方面的专业知识：血小板减少症的护理和管理。 （摘要完）