Novel signaling molecules regulating platelet activation

调节血小板活化的新型信号分子

• 批准号: 10851106
• 负责人: Satya P. Kunapuli
• 金额: $ 5.61万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10851106
• 关键词: American; Animal Model; Animals; Antibiotics; Atherosclerosis; Bacteriology; Biomedical Research; Black race; Blood; Blood Platelets; Disease; Doctor of Philosophy; Education; Endocarditis; Enterococcus; Enterococcus faecalis; Gastrointestinal tract structure; Glycoprotein Ib; Goals; Grant; Haitian; Health; Hemostatic function; Human; Infection; Inflammation; Laboratories; Lead; Malignant Neoplasms; Mediating; Microbial Biofilms; Minority Groups; Mobile Genetic Elements; Modeling; Multi-Drug Resistance; Oryctolagus cuniculus; Parents; Pathogenicity; Pathway interactions; Patients; Pheromone; Phosphorylation; Plasmids; Platelet Activation; Play; Production; Protein Tyrosine Kinase; Regulation; Research; Research Design; Risk; Role; Scientist; Sepsis; Septicemia; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Staphylococcus aureus; Stream; Structure; Surface; Thrombosis; Thromboxane A2; Training; Underrepresented Minority; Variant; Viscosity; career; design; heart dimension/size; interest; member; mortality; mouse model; novel; opportunistic pathogen; parent grant; pathogen; recruit; role model; thrombotic

The purpose of this Research Supplement to Promote Diversity in Health-Related Research is to support a project of the applicant which is an extension of the research parent R35 grant. The applicant is Haitian American citizen and a member of the Black underrepresented minority group. Platelets play a crucial role in hemostasis and thrombosis, and more and more studies indicate their role in other disease states including inflammation, cancer, and atherosclerosis. The R35 focuses on these signaling steps and how their interplay mediates platelet activation. Understanding signaling networks and their regulation has been my research focus for the past two decades and our group has made important contributions to the platelet-signaling field. The goal of the R35 is to identify novel signaling molecules that regulate main signaling pathways, characterize novel signaling pathways emanating from the same signaling molecule, and understand the differences in various tyrosine kinase pathways in platelets. The research design for the supplement grant follows the original studies constituting the parent grant and will be focused on research discovering novel signaling mechanisms provided by structures within bacterial biofilms which can increase platelet activation. Enterococcal septicemia, predominantly caused by E. faecalis, can be difficult to treat with antibiotics and lethality approaches 25% of patients if the infection is not resolved in 30 days. This lethality rate is significantly higher than S. aureus, and the basis of the increased mortality is not known. Not all E. faecalis blood stream infections lead to septicemia suggesting there may be strain to strain variation. E. faecalis strains range from ubiquitous commensals of the gastrointestinal tract to multidrug resistant nosocomial pathogens. Mobile genetic elements play an important role in converting commensal E. faecalis into nosocomial multidrug resistant (MDR) opportunistic pathogens. Pheromone responsive plasmids can be present in >60% of characterized pathogenic isolates and are correlated with increased size of heart vegetations in endocarditis rabbit models by unknown mechanisms. During the applicant's master studies in a basic bacteriology laboratory, the applicant discovered the plasmid pCF10 remodeling the E. faecalis biofilm producing densely packed rigid structures within viscous surface-attached biofilms and lead to the production of nonattached biofilm aggregates containing viscous biofilms with rigid structures. For the Ph.D. the applicant wants to do biomedical research including animal modeling and human platelets. The central hypothesis is that rigid structures in biofilms and biofilm aggregates, activate platelets by three unique mechanisms, tugging effects of multiple sites on the glycoprotein Ib/V/IX to generate thromboxane A2 (Aim 1) and PKC for platelet activation and Y155 phosphorylation for inflammation will both contribute to increasing thrombotic risk leading to sepsis in animals infected with plasmid-containing strains (Aim 2). Completion of this project will aid the candidate in establishing a career in biomedical disease research and, with an interest in education, the candidate will serve as a role model for further recruitment and training of URM scientists.

本研究增刊旨在促进健康相关研究的多样性，旨在支持 申请人的项目是研究母公司R35资助的延伸申请人是海天美国公司。 公民和黑人少数群体的成员 血小板在止血中发挥着至关重要的作用。 和血栓形成，越来越多的研究表明它们在其他疾病状态中的作用，包括炎症、 R35 专注于这些信号传导步骤以及它们如何相互作用介导血小板。 了解信号网络及其调控一直是我过去两年的研究重点。 几十年来，我们的团队为血小板信号传导领域做出了重要贡献。R35 的目标是： 识别调节主要信号通路的新型信号分子，表征新型信号通路 源自相同的信号分子，并了解各种酪氨酸激酶的差异 补充资助的研究设计遵循构成血小板的原始研究。 家长资助，将专注于发现结构提供的新颖信号机制的研究 细菌生物膜内可增加血小板活化，主要由肠球菌引起。 由粪肠球菌感染，用抗生素治疗可能会很困难，如果感染是的话，致死率接近 25% 30天内未解决此致死率明显高于金黄色葡萄球菌，且基础增加。 死亡率尚不清楚，并非所有粪肠球菌血流感染都会导致败血症，这表明可能存在败血症。 菌株之间的变异。粪肠球菌菌株的范围从胃肠道普遍存在的共生菌到 多重耐药医院病原体在转化中发挥着重要作用。 共生粪肠球菌转化为医院内多重耐药（MDR）机会性病原体。 响应性质粒可以存在于 >60% 的特征性致病分离株中，并且与 在心内膜炎兔子模型中，心脏赘生物的大小通过未知的机制增加。 申请人在基础细菌学实验室攻读硕士学位时，申请人发现了质粒pCF10 重塑粪肠球菌生物膜，在粘性表面附着内产生密集的刚性结构 生物膜并导致产生含有刚性粘性生物膜的非附着生物膜聚集体 对于博士学位，申请人想要进行生物医学研究，包括动物建模和人体研究。 中心假设是生物膜和生物膜聚集体中的刚性结构通过激活血小板。 三种独特的机制，糖蛋白 Ib/V/IX 上多个位点的牵引作用以产生血栓素 用于血小板活化的 A2（目标 1）和 PKC 以及用于炎症的 Y155 磷酸化都有助于 增加血栓形成风险，导致感染含质粒菌株的动物败血症（目标 2）。 该项目的完成将帮助候选人建立生物医学疾病研究的职业生涯，并具有 对教育感兴趣，候选人将成为进一步招募和培训 URM 科学家的榜样。