Pathogenesis of thrombotic microangiopathies

血栓性微血管病的发病机制

基本信息

批准号：
10608740
负责人：
X. Long Zheng
金额：
$ 51.91万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2023-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608740
关键词：
5&apos Untranslated Regions ADAMTS Acute Adrenal Cortex Hormones Agglutination Allosteric Regulation Animal Model Antibodies Ants Autoantibodies B-Lymphocytes Binding Biochemical Biological Biological Process Blood Blood Platelets Blood capillaries Cessation of life Chromium Clonality Code Disease Disease remission Disintegrins Elements Endothelial Cells Endothelium Evolution Family Flow Cytometry Future Gene Family Generations Genetic Genomics Goals Hematological Disease Hematopoiesis Hemolytic Anemia Hemostatic Agents Hepatic Stellate Cell Human Immune Immunoglobulin G Immunoglobulin Variable Region Immunoglobulins Immunological Models Immunologics Inflammation Inflammatory Response Inherited Knowledge Mass Spectrum Analysis Mediating Megakaryocytopoieses Memory B-Lymphocyte Metalloproteases Molecular Molecular Profiling Monoclonal Antibodies Morbidity - disease rate Mutation Outcome Pathogenesis Pathology Patients Phenotype Plasma Plasmapheresis Production Protein Family Proteome Publishing Reagent Refractory Disease Role Stream Structure Testing Therapeutic Intervention Thrombocytopenia Thrombosis Thrombospondins Thrombotic Thrombocytopenic Purpura Thrombus V(D)J Recombination Zebrafish arteriole biophysical techniques complementarity-determining region 3 experience gain of function human monoclonal antibodies loss of function member mortality mouse model nanobodies novel novel therapeutic intervention organ injury rituximab sequencing platform standard of care thrombogenesis thrombotic tool von Willebrand Factor

项目摘要

PROJECT SUMMARY Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves endothelial von Willebrand factor. Despite progresses being made in past decades, major gap remains in our understanding the pathogenesis of iTTP. The proposed study will test the hypotheses that: 1) distinct molecular signatures in the complementarity determining region (CDR)-3 and the VDJ rearrangements in the variable regions of immunoglobulins (Ig) against ADAMTS13 determine their functionalities (e.g., the inhibitory vs. activating) in patients with iTTP; 2) the abnormalities in ANKRD26 and 36 gene family, initially identified to associate with hereditary thrombocytopenia, may also play a role in pathogenesis of iTTP, likely through disruption of megakaryocytopoiesis and enhanced immune inflammatory responses. The proposed study will use various cutting-edge tools and animal models to test these hypotheses. The results of the proposed study will shed new light on pathogenesis of iTTP and other immune thrombotic disorders. The findings may help develop novel strategies for therapeutic interventions for such disorders.

项目概要免疫性血栓性血小板减少性紫癜（iTTP）是一种罕见但可能致命的血液疾病，导致来自 ADAMTS13 自身抗体，ADAMTS13 是一种血浆金属蛋白酶，可裂解内皮血管性血友病因素。尽管过去几十年取得了进展，但我们对这一问题的理解仍然存在重大差距 iTTP 的发病机制。拟议的研究将检验以下假设：1）互补决定区（CDR）-3和可变区中的VDJ重排针对 ADAMTS13 的免疫球蛋白 (Ig) 决定其功能（例如，抑制与激活） iTTP 患者； 2) ANKRD26和36基因家族的异常，初步确定与遗传性血小板减少症也可能在 iTTP 的发病机制中发挥作用，可能是通过破坏巨核细胞生成和增强的免疫炎症反应。拟议的研究将使用各种检验这些假设的尖端工具和动物模型。拟议研究的结果将揭示 iTTP 和其他免疫血栓性疾病发病机制的新线索。研究结果可能有助于发展针对此类疾病的治疗干预的新策略。