Molecular and Translational Studies in Hematologic Disorders

血液疾病的分子和转化研究

• 批准号: 10593910
• 负责人: Jose Aron Lopez
• 金额: $ 108.01万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593910
• 关键词: ADAMTS; Acetylcysteine; Affect; Amino Acids; Animal Model; Area; Award; Blood; Blood Platelets; Defect; Disease; Erythrocytes; Family; Food; Funding Mechanisms; Goals; Grant; Hematological Disease; Hemorrhage; Hemostatic Agents; Lesion; Measures; Metalloproteases; Molecular; Mutation; National Heart, Lung, and Blood Institute; Nature; Oxidative Stress; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Plasma Proteins; Proteolysis; Regulation; Research Personnel; Role; Sickle Cell Anemia; Spectrin; Testing; Work; expectation; fascinate; flexibility; human disease; improved; member; monomer; mutant; tool; translational study; von Willebrand Disease; von Willebrand Factor

This application for an NHLBI R35 Outstanding Investigator Award is to explore the role of the plasma protein von Willebrand factor (VWF) in 2 diseases, type 2 von Willebrand disease (VWD) and sickle cell disease (SCD), and our goal is to roll 2 R01 grants covering these areas into a single, more cohesive grant with more flexibility to follow interesting scientific leads. In these two diseases, the involvement of VWF is in opposite directions, dysfunctional and with predominantly small multimers in type 2 VWD, and abundant, hyperfunctional, and large in sickle cell disease. For VWD, we will explore the molecular basis of the broad phenotypic variability associated with single mutations, testing the hypothesis that important determinants of this variability include percentage of mutant monomer incorporation into multimeric VWF and extent of VWF proteolysis by the met- alloprotease ADAMTS13. We will also explore how platelet contractility is affected in type 2 VWD, including to determine the respective contributions of plasma and platelet VWF. Finally, we will examine the intriguing possibility that in types 2A and 2B VWD a significant contribution to the hemostatic defect is provided by VWF fragments produced by excessive VWF proteolysis. In SCD, we have evidence of defective regulation of the largest VWF multimers, which are inadequately cleaved by ADAMTS13. We will investigate the basis of this lesion, and test whether a variety of measures aimed at attenuating the activity of VWF will improve the course of the disease in an animal model of SCD. Finally, we will explore the molecular basis of a fascinating observation we made in the course of studying the effect of N-acetylcysteine in SCD: that the drug induced rapid loss of very dense erythrocytes from the blood of patients. We hypothesize that the effect is caused by reduction of oxidized spectrin residues and will also explore the possibility that it may be treated even more effectively by the amino acid L-ergothioneine, which is present in mushrooms and other foods and is concen- trated in erythrocytes by a highly specific transporter. Together, these studies use state-of-the-art tools to ex- plore perplexing problems in two important human diseases, with the expectation of improved therapies for the affected patients. The R35 funding mechanism provides the flexibility to follow interesting leads discov- ered during the course of these studies, increasing the likelihood that patients will benefit.

NHLBI R35杰出研究者奖的申请是探索血浆蛋白的作用 2种疾病，2型von Willebrand疾病（VWD）和镰状细胞疾病（SCD）的冯·威尔布兰德因子（VWF）， 我们的目标是滚动2 R01赠款，将这些区域覆盖为一个更具凝聚力的赠款，并具有更大的灵活性 遵循有趣的科学线索。在这两种疾病中，VWF的参与是相反的， 功能失调，主要是2型VWD中的多聚体，并且丰富，功能过高，并且 镰状细胞病大。对于VWD，我们将探索广泛表型变异性的分子基础 与单个突变有关，检验了这种可变性重要决定因素的假设包括 突变单体掺入多聚体VWF的百分比以及通过Met-的VWF蛋白水解程度 同蛋白酶ADAMTS13。我们还将探讨在2型VWD中如何影响血小板的收缩力，包括 确定血浆和血小板VWF的各自贡献。最后，我们将研究有趣的 在2A型和2B vwd中，可能对止血缺陷做出重大贡献。 VWF片段由过度的VWF蛋白水解产生。在SCD中，我们有证据表明对 最大的VWF多聚体，ADAMTS13裂解不足。我们将调查 这种病变，并测试旨在减弱VWF活动的各种措施是否会改善 SCD动物模型中的疾病过程。最后，我们将探索引人入胜的分子基础 我们在研究N-乙酰半胱氨酸在SCD中的作用的过程中进行了观察：该药物诱导 从患者血液中快速丧失非常密集的红细胞。我们假设效果是由 还原氧化光谱残基，还将探讨它可以得到更多处理的可能性 有效地由氨基酸l-甲基氨基氨酸，它存在于蘑菇和其他食物中，并有点 由高度特异性转运蛋白在红细胞中表现出来。这些研究一起使用最先进的工具来进行 在两种重要的人类疾病中，使人困惑的问题令人困惑，并期望改善疗法 受影响的患者。 R35资金机制提供了遵循有趣的线索的灵活性 - 在这些研究的过程中，增加了患者受益的可能性。