Molecular and Translational Studies in Hematologic Disorders

血液疾病的分子和转化研究

• 批准号: 9894847
• 负责人: Jose Aron Lopez
• 金额: $ 108.46万
• 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/9894847
• 关键词: Acetylcysteine; Affect; Amino Acids; Animal Model; Area; Attenuated; Award; Blood; Blood Platelets; Cleaved cell; 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; Oxides; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Plasma Proteins; Proteolysis; Regulation; Research Personnel; Role; Sickle Cell Anemia; Spectrin; Testing; Work; cohesion; 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为了探索血浆蛋白的作用， 血管性血友病因子（VWF）在2种疾病中的作用，2型血管性血友病（VWD）和镰状细胞病（SCD）， 我们的目标是将覆盖这些领域的2个R01赠款合并为一个单一的、更具凝聚力的、更具灵活性的赠款 去追踪有趣的科学线索在这两种疾病中，VWF的参与方向相反， 在2型VWD中，功能障碍和主要是小的多聚体，以及丰富的，功能亢进的， 在镰状细胞病中很常见对于VWD，我们将探索广泛表型变异的分子基础 与单突变相关，检验这种变异性的重要决定因素包括 突变体单体掺入多聚体VWF的百分比和met- 别蛋白酶ADAMTS13。我们还将探讨2型VWD中血小板收缩性如何受到影响，包括 以确定血浆和血小板VWF各自的贡献。最后，我们将研究有趣的 在2A型和2B型VWD中，止血缺陷的显著贡献可能由以下因素提供： 过度的VWF蛋白水解产生的VWF片段。在SCD中，我们有证据表明， 最大的VWF多聚体，其被ADAMTS13不充分切割。我们将调查 这种病变，并测试旨在减弱VWF活性的各种措施是否会改善这种病变 在SCD动物模型中的疾病过程。最后，我们将探索一种迷人的 在研究N-乙酰半胱氨酸对SCD的作用过程中，我们观察到： 患者血液中非常致密的红细胞的快速损失。我们假设这种影响是由以下因素引起的 氧化血影蛋白残留物的减少，也将探讨它可能被处理的可能性，甚至更多 有效地通过氨基酸L-麦角硫因，这是目前在蘑菇和其他食物，是集中， 在红细胞中通过高度特异性的转运蛋白进行转运。总之，这些研究使用了最先进的工具， 探索两种重要人类疾病中令人困惑的问题，期望改进治疗方法， 受影响的患者。R35供资机制提供了跟踪有趣线索发现的灵活性- 在这些研究过程中，增加了患者受益的可能性。