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Examination of the Final Stages of Platelet Production

血小板生产最后阶段的检查

基本信息

批准号：
8720054
负责人：
JONATHAN N THON
金额：
$ 13.31万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720054
关键词：
3-Dimensional Actins Address Aplastic Anemia Appointment Authorization documentation Automobile Driving Biochemistry Biological Birth Blood Blood Circulation Blood Platelet Disorders Blood Platelets Blood Vessels Blood flow Bone Marrow British Columbia Caliber Cell Culture Techniques Cells Cellular biology Clinical Collection Cytoskeleton Data Degradation Pathway Deterioration Development Development Plans Doctor of Philosophy Dynein ATPase Dysmyelopoietic Syndromes Electron Microscopy Endothelial Cells Environment Environmental Risk Factor Equipment Excision Extracellular Matrix Extracellular Matrix Proteins F-Actin Fluorescence Microscopy Functional disorder Goals HIV Hemorrhage Hemostatic function Hospitals Human Immune Immune response In Vitro Individual Infection Infusion procedures Inherited Institutes Integrins Joints Laboratories Lead Life Mechanics Mediating Megakaryocytes Membrane Mentors Mentorship Microtubules Modeling Molecular Molecular Biology Molecular Biology Techniques Operative Surgical Procedures Outcome Pathway interactions Patients Pattern Phase Platelet Count measurement Platelet Transfusion Play Postdoctoral Fellow Pregnancy Process Production Property Proteins Proteomics Public Health Recruitment Activity Regulation Relative (related person)Research Research Personnel Resistance Risk Role Running Scientist Services Shapes Side Signal Pathway Signal Transduction Site Slide Source Spectrin Staging Surface System Techniques Thrombocytopenia Thrombocytopenic Purpura Thrombosis Training Training Programs Transgenic Mice Translations United States Universities Vascular Endothelial Cell Venous Virus Diseases Woman Work Writing arm base biochip career career development cellular imaging chemotherapy design drug testing experience improved in vitro Model in vivo interest medical schools meetings membrane skeleton mimetics mouse model polymerization professor programs protein complex receptor research study skills

项目摘要

DESCRIPTION (provided by applicant): Examination of the Final Stages of Platelet Production Candidate. My Ph.D. thesis, under the direction of Dr. Dana Devine (Professor, University of British Columbia; Vice President, Canadian Blood Services), entailed the application of proteomics, molecular biology, and biochemistry to identify mechanisms involved in regulating the storage-related deterioration of platelets (PLTs). In Dana's lab I worked closely with Canadian Blood Services, clinicians, and investigators at the Centre for Blood Research to improve the collection, processing, and storage of blood PLTs. My post-doctoral research in Dr. Joseph Italiano's laboratory (Associate Professor, Harvard University), has added to my repertoire a number of specialized cell biology techniques including fluorescence and electron microscopy, live cell imaging, retroviral infection, cell culture, and transgenic mouse models to study PLT production. These projects have provided me with the necessary expertise to meet my career goals by familiarizing me with the cytoskeletal mechanics, contribution of environmental factors such as extracellular matrix (ECM) components and shear forces, and the signaling pathways that orchestrate PLT formation and regulate their function. Environment. Dr. Italiano's laboratory has offered unequalled access to an extensive network of exceptionally talented PLT researchers whose input and experience have helped guide my research and allowed me to markedly expand my arsenal of analytical, management, writing, and oratory skills. Dr. Italiano has also made available to me a range of highly specialized equipment, armed me with a number of molecular biology techniques that are complementary to my research goals, and provided me with dedicated mentorship that has enabled me to become an accomplished PLT biologist and microscopist. The opportunity to train at an institute that is world-renowned for its PLT work has allowed me to establish meaningful collaborative relationships with PLT researchers worldwide. My joint appointment at Harvard Medical School and Brigham and Women's Hospital has afforded me access to a multitude of courses, internal training programs, departmental seminars, and career development and educational programs that have made me a better scientist, and supported my career trajectory toward independent investigator. Research. Blood PLTs play an essential role in hemostasis and the pathophysiology of thrombosis. My interests lay in investigating the mechanisms of PLT formation for the purpose of developing targeted therapies for thrombocytopenia. The ability to control in vitro megakaryocyte (MK) expansion and maturation into PLTs will result in an important source of PLTs for infusion. My short-term goals are to investigate the final stages of PLT production, for which a research plan comprising three specific aims is proposed. MKs release long branched extensions called proPLTs into sinusoidal blood vessels that undergo repeated abcissions to yield circulating PLTs. Aim 1 will examine the cytoskeletal mechanics by which individual PLTs are released from proPLTs. These experiments will address the microtubule, and filamentous-actin-based forces that power proPLT extension and PLT release both in live cells and within a permeabilized cell system. Aim 2 will model how MKs establish polarity and direct proPLTs toward sinusoidal blood vessels to deliver PLTs into the circulation. Aim 3 will resolve the contribution of environmental factors such as ECM interactions and continuous blood flow in generating functional PLTs and regulating their rate/extent of release. Research career development plan. Research on aim 1 will commence during the mentored (K99) phase, with aim 1.3 continuing into the independent (R00) phase. The goals described in aims 1.1 and 1.2 represent a mentored departure from the research aims of my primary supervisor, which will run parallel to my work and focus on protein translation/degradation pathways that initiate proPLT production, and the role of the spectrin- based membrane skeleton on PLT formation. Research on aim 2 will also commence during the mentored phase and proceed into the first year of the independent phase, to bridge the gap between the cytoskeletal and environmental determinants of proPLT extension and PLT release. The preliminary data deriving from aims 1 and 2 will allow me to launch an independent research program in year 3 to recapitulate the bone marrow and sinusoidal blood vessel microenvironments in vitro and study their role in terminal PLT production (aim 3.1 and 3.2). Research on aim 3.3 will commence in year 3, after initial biochip development, and will examine the quality of culture-derived PLTs with each new advancement in biochip design. These data will support my long-term career goals of (1) developing bio-mimetic systems to generate useable numbers of clinically viable human PLTs for infusion, and (2) establishing representative ex vivo models of human bone marrow and surrounding vasculature for the purposes of testing drugs and developing targeted therapies for thrombocytopenia. Neither the specific aims nor the research goals listed in this application overlap with those of my mentors, and I have recieved permission to take them with me to my own research lab.

描述（由申请人提供）：血小板生产候选药物最后阶段的检查。我的博士论文是在Dana Devine博士（英属哥伦比亚大学教授，加拿大血液服务中心副主席）的指导下完成的，涉及到蛋白质组学、分子生物学和生物化学的应用，以确定血小板（PLTs）储存相关退化的调节机制。在戴娜的实验室里，我密切合作