Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis

炎症、止血和血栓形成的细胞机制

• 批准号: 10676869
• 负责人: Mark HOWARD Ginsberg
• 金额: $ 233.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676869
• 关键词: Adhesives; Adult; Blood; Blood Platelets; Blood Vessels; CCM1 gene; Cell Adhesion; Cell physiology; Cell-Cell Adhesion; Cells; Collaborations; Complex; Development; Endothelial Cells; Endothelium; Event; Gene Silencing; Genes; Genetic; Glass; Heart; Hemostatic function; Human; Individual; Inflammation; Leukocyte Adhesion Deficiency; Leukocytes; Methods; Microfluidics; Molecular; Molecular Conformation; Mus; Mutate; Play; Prevention strategy; Process; Regulation; Research Personnel; Resistance; Role; Signal Transduction; Structural Biologist; Structure; Surface; Talin; Testing; Therapeutic; Thrombosis; Translations; Ubiquitination; Vascular Diseases; adhesion receptor; design; experience; feasibility testing; imaging modality; improved outcome; in vivo; in vivo Model; mouse model; neutrophil; novel; novel diagnostics; novel therapeutic intervention; optogenetics; pharmacologic; platelet function; programs; protein protein interaction; response; superresolution imaging

ABSTRACT Support is requested for an interdisciplinary effort to understand the key molecular and developmental events that regulate blood and vascular cells in inflammation, hemostasis and thrombosis with a focus on adhesive signaling. The four Projects will: 1) Test the hypothesis that direct interactions between Rap1 and talin1 plays an important role in platelet, leukocyte, and endothelial cell functions in inflammation, hemostasis and thrombosis. 2) Use newly developed imaging modalities to enable quantitative dynamic footprinting of the surface of neutrophils in contact with substrate to assess adhesion receptor clustering and conformation in response to specific molecular adaptor-adhesion receptor interactions. A particular focus is the structure-function of kindlin-3, the gene mutated in human leukocyte adhesion deficiency Type 3, and its relationship to talin. 3) An Early Stage Investigator will test the hypothesis that genetic inactivation of Krit1 or Heg1 in adult mice will protect against experimental inflammation or thrombosis. In collaboration with a structural biologist, he will extend studies to test the feasibility of pharmacologically disrupting the HEG1-KRIT1 complex to mimic the effects of genetic inactivation of these genes. 4) To assess the role of SHARPIN and associated components of the LUBAC linear ubiquitination complex in the functions of platelets and endothelial cells in inflammation, hemostasis, and thrombosis. This project will test the hypothesis that this newly-identified regulator of platelet and endothelial cell functions contributes to inflammation, hemostasis, and thrombosis. A scientific core unit, led by a world leader in murine models of inflammation, hemostasis, and thrombosis, will provide the individual projects with in vivo models and expertise required to establish the patho- physiological relevance of these novel molecular mechanisms.

抽象的 需要支持跨学科的努力来了解关键的分子和 调节血液和血管细胞炎症、止血的发育事件 和血栓形成，重点关注粘附信号传导。这四个项目将： 1) 测试 假设 Rap1 和 talin1 之间的直接相互作用在 血小板、白细胞和内皮细胞在炎症、止血和 血栓形成。 2）使用新开发的成像方式来实现定量动态 中性粒细胞与基质接触表面的足迹以评估粘附力 响应特定分子接头粘附的受体聚类和构象 受体相互作用。特别关注的是 kindlin-3（基因）的结构功能 人类白细胞粘附缺陷3型中的突变及其与talin的关系。 3） 早期研究人员将检验 Krit1 或基因失活的假设 成年小鼠中的 Heg1 可以防止实验性炎症或血栓形成。在 与结构生物学家合作，他将扩展研究以测试其可行性 通过药理作用破坏 HEG1-KRIT1 复合物以模拟遗传效应 这些基因的失活。 4) 评估SHARPIN和相关的作用 LUBAC 线性泛素化复合物的成分在血小板和功能中的作用 内皮细胞在炎症、止血和血栓形成中的作用。该项目将测试 假设这种新发现的血小板和内皮细胞功能调节剂 有助于炎症、止血和血栓形成。科学核心单位，由 炎症、止血和血栓形成小鼠模型的世界领先者，将提供 具有建立病理所需的体内模型和专业知识的单个项目 这些新分子机制的生理相关性。

项目成果

Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC.

• DOI: 10.1182/bloodadvances.2021005611
• 发表时间: 2022-04-26
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Kasirer-Friede A;Peuhu E;Ivaska J;Shattil SJ
• 通讯作者: Shattil SJ

Neutrophil ion currents matter.

中性粒细胞离子流很重要。

• DOI: 10.1093/cvr/cvac025
• 发表时间: 2022
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Ley,Klaus

Small matters: Introduction to extracellular vesicles.

小事：细胞外囊泡简介。

• DOI: 10.1111/imr.13140
• 发表时间: 2022
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Ley,Klaus;Boulanger,ChantalM
• 通讯作者: Boulanger,ChantalM

The expanding family of neutrophil-derived extracellular vesicles.

• DOI: 10.1111/imr.13103
• 发表时间: 2022-11
• 期刊: Immunological reviews
• 影响因子: 8.7

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.

• DOI: 10.1021/acsptsci.3c00156
• 发表时间: 2023-10
• 期刊: ACS pharmacology & translational science
• 影响因子: 6
• 作者: Karol R. Francisco;J. Bruystens;C. Varricchio;Sara McCurdy;Jian Wu;M. Lopez-Ramirez;Mark Ginsberg;Conor R. Caffrey;Andrea Brancale;Alexandre R. Gingras;Mark S. Hixon;C. Ballatore