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（由申请人提供）：血小板的分泌是正确的止血的关键过程，即血小板分泌所需的snare蛋白质，几乎没有理解在血小板激活时进行的重新调节。血小板依赖性分泌物。血小板中的信号和血栓形成。蛋白酶体/PSMC1在血小板上和血栓形成中，我们将采用大量的海滩，遗传学和药理学工具和方法，以定义新的治疗剂和/或新的目标来管理势不足的疾病，我们将采用大量的海滩，遗传和药理学工具和方法。 。

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