Regulation of Platelet SNARE Machinery

血小板圈套机械的调节

• 批准号: 9022322
• 负责人: Zubair A Karim
• 金额: $ 42.19万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-12 至 2016-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022322
• 关键词: 26S proteasome; ATP phosphohydrolase; Address; Alpha Granule; Beryllium; Biochemical; Biochemical Genetics; Biology; Blood Platelets; Cell Surface Receptors; Cell membrane; Cells; Complex; Cytoplasmic Granules; Development; Disease; Exocytosis; Foundations; Goals; Heart Diseases; Hemostatic Agents; Hemostatic function; Intervention; Investigation; Life; Link; Mediating; Medical; Membrane; Membrane Microdomains; Membrane Proteins; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Nature; Pathway interactions; Phosphotransferases; Physiological; Platelet Activation; Play; Polyubiquitination; Prevention; Process; Proteasome Inhibitor; Proteins; Regulation; Role; SNAP receptor; Scaffolding Protein; Signal Transduction; Signaling Molecule; Site; Stimulus; Stroke; Testing; Therapeutic; Therapeutic Agents; Thrombosis; Ubiquitination; base; design; genetic approach; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutics; public health relevance; receptor; research study; response; scaffold; therapeutic target; tool

 DESCRIPTION (provided by applicant):Secretion from platelets is a critical process required for correct hemostasis. While several studies have shown that SNARE proteins are required for platelet secretion, little is understood about how they are regulated upon platelet activation. Nonetheless, we have previously identified the IKK pathway as a key regulator of platelet SNARE-dependent secretion. And subsequently shown that the scaffolding protein MALT1 is ubiquitinated and regulates IKK activity, and SNARE complex formation, in platelets. Thus, we hypothesize that IKK and upstream signaling molecules are present in platelets and play an important role in platelet exocytosis, and the genesis of thrombosis. We further hypothesize that proteasome/PSMC1 plays an important role in NF-ƘB/IKK signaling in platelet and in thrombogenesis. The following Aims are designed to test our hypothesis: Specific Aim I: Delineate the signaling elements that are upstream of IKK activation and assess the biochemical ramification of IKK activation and regulation of SNARE complex formation in stimulated platelets. Specific Aim II: Investigate the function of the proteasome/PSMC1 in platelet activation and thrombogenesis. To accomplish these translationally-relevant aims, we will employ a host of biochemical, genetic and pharmacological tools and approaches, with the ultimate goal of defining new therapeutic agents and/or novel targets for the management of thrombotic disorders.

 描述（适用提供）：血小板的分泌是正确止血所需的关键过程。虽然几项研究表明血小板分泌所需的核心蛋白是关于血小板激活后如何调节它们的几乎几乎没有理解的。但是，我们以前已经将IKK途径确定为血小板依赖性分泌的关键调节剂。随后表明，脚手架的蛋白质是泛素化的，并调节了IKK活性，并在血小板中进行了ick依复合物的形成。这就是我们假设IKK和上游信号分子存在于血小板中，并且在血小板外胞胞菌病和血栓形成的起源中起着重要作用。我们进一步假设蛋白酶体/PSMC1在血小板和血栓形成中NF-ƙB/IKK信号传导中起重要作用。以下目的旨在检验我们的假设：特定目的I：描述IKK激活上游的信号传导元素，并评估IKK激活和调节刺激血小板中的SNARE复合物形成。特定目标II：研究蛋白酶体/PSMC1在血小板激活和血栓形成中的功能。为了实现这些相关的目标，我们将采用大量的生化，遗传和药品工具和方法，其最终目标是定义新的治疗剂和/或新颖的目标来管理血栓性疾病。

项目成果

Role of IκB kinase β in regulating the remodeling of the CARMA1-Bcl10-MALT1 complex.

IκB 激酶 β 在调节 CARMA1-Bcl10-MALT1 复合物重塑中的作用。

• DOI: 10.1016/j.bbrc.2018.04.057
• 发表时间: 2018
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Karim,ZubairA;Hensch,NicoleR;Qasim,Hanan;Alshbool,FatimaZ;Khasawneh,FadiT
• 通讯作者: Khasawneh,FadiT