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Basic Investigation and Translational Applications Concerning the Cell and Molecular Biology of Blood and Vascular Cells

有关血液和血管细胞的细胞和分子生物学的基础研究和转化应用

基本信息

批准号：
10593173
负责人：
Peter J Newman
金额：
$ 98.66万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593173
关键词：
Acute Adhesives Affinity Animal Model Antigen Presentation Binding Blood Blood Cells Blood Coagulation Disorders Blood Platelets Blood Vessels CD31 Antigens CRISPR/Cas technology Cell Adhesion Cell Line Cell physiology Cells Cellular biology Cessation of life Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cryopreservation Development Diagnosis Diagnostic Disease Endothelial Cells Extravasation Fetus Functional disorder Future Genes Glues Hematological Disease Human Human Platelet Antigens Immune Targeting Immune system Infant Inflammation Inflammatory Inherited Intercellular Junctions Intracranial Hemorrhages Investigation Liquid substance Maternal antibody Megakaryocytes Mission Modeling Molecular Biology Molecular Conformation Movement National Heart, Lung, and Blood Institute Neonatal Neonatal Alloimmune Thrombocytopenia PECAM1 gene Placenta Principal Investigator Proteins Receptor Signaling Reperfusion Injury Research Role Sepsis Series Source Speed Surface Technology Therapeutic Thrombocytopenia Tissues Transfusion Vascular Diseases Vascular Permeabilities biological adaptation to stress design diagnostic platform disability fetal humanized mouse improved induced pluripotent stem cell innovation interest isoimmunity mouse model neonatal care neonate new therapeutic target novel novel diagnostics personalized therapeutic programs receptor receptor function response restoration self-renewal stem cells three dimensional structure thrombotic tool translational applications

项目摘要

Studies proposed in this application encompass and extend long-standing interests of the Principal Investigator in the cell and molecular biology of blood and vascular cells. The proposed Program is comprised of two ambitious, impactful projects designed to fill important conceptual gaps in their respective fields, and that have long been judged to be of interest and relevance to the overall mission of the NHLBI; namely (1) The role of PECAM-1 in vascular cell function, and (2) The pathophysiology of neonatal alloimmune thrombocytopenia (NAIT). PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor that functions in circulating blood cells to limit the rate and extent of cellular activation. PECAM-1 is also the most highly-expressed component of the endothelial cell-cell junction, where it functions as a homophilic adhesive stress-response protein to maintain endothelial cell junctional integrity and speed restoration of the vascular permeability barrier following inflammatory or thrombotic challenge. We will exploit our recent determination of the three-dimensional structure of the PECAM-1 homophilic binding domain, our development of innovative PECAM-1-targeted tools and animal models, and our discovery that PECAM-1 is subject to conformational affinity modulation to examine the potential for PECAM-1 to serve as a novel therapeutic target for a wide range of vascular permeability disorders, including sepsis-induced vascular leakage and ischemia-reperfusion injury. This Program will also focus on developing new tools, models and treatments for NAIT – a rare, but catastrophic, clinically important bleeding disorder caused by maternal antibodies generated in response to paternally-inherited antigens present on fetal platelets that re-cross the placenta and bind to fetal and/or neonatal platelets, resulting in thrombocytopenia often serious enough to require transfusion, and in the most severe cases causing intracranial hemorrhage and intrauterine death. Despite advances in treatment, NAIT remains the leading cause of intracranial hemorrhage in full-term infants, often leading to lifelong disability. We propose to combine recent transformative advances in CRISPR gene editing technology with the ability to generate megakaryocyte progenitor cells, megakaryocytes, and platelets from induced pluripotent stem cells to establish a transformative diagnostic platform designed to narrow the existing “diagnostic gap” to improve treatment and care of NAIT - namely the creation of platelet alloantigen-specific cell lines capable of long-term self-renewal, cryopreservation, and distribution; thereby providing a potentially inexhaustible source of iPS-derived platelets for diagnostic, investigative, (and potentially future therapeutic) use. CRISPR technology has also allowed us to develop a novel humanized mouse model of NAIT that will allow us to resolve a series of outstanding issues in platelet alloimmunity. Taken together, this research program will apply cutting-edge technology to lay the groundwork for continuing advances in the diagnosis and treatment of these and related blood and vascular disorders of relevance to the mission of the National Heart, Lung and Blood Institute.

本申请中提出的研究包括并扩展了校长的长期利益