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.

这项研究补充促进与健康相关研究多样性的目的是支持 申请人的项目是研究父母R35赠款的扩展。申请人是海地美国人 公民和黑人代表性不足的少数群体的成员。血小板在止血中起着至关重要的作用 和血栓形成，以及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， 癌症和动脉粥样硬化。 R35专注于这些信号步骤以及它们的相互作用如何介导血小板 激活。了解信号网络及其监管一直是我过去两个的研究重点 几十年来，我们的小组为血小板信号田做出了重要贡献。 R35的目标是 确定调节主要信号通路的新型信号分子，表征新的信号通路 从相同的信号分子发出，并了解各种酪氨酸激酶的差异 血小板中的途径。补充补助金的研究设计遵循的原始研究构成了 父母赠款，将重点放在研究结构提供的新型信号机制的研究上 在细菌生物膜中可以增加血小板激活。肠球菌败血症，主要引起 通过大肠杆菌，如果感染是抗生素，可能很难用抗生素治疗25％的患者 在30天内未解决。这种致死率明显高于金黄色葡萄球菌，并且是增加的基础 死亡率尚不清楚。并非所有的粪肠球菌血流感染都会导致败血病，表明可能存在 应变变异。大肠杆菌菌株范围从胃肠道的普遍存在到 多药耐药的医院病原体。移动遗传元素在转换中起重要作用 共生大肠杆菌进入医院多药（MDR）机会病原体。信息素 反应质质粒可以存在于> 60％的特征性致病株中，并与 通过未知机制，心内膜炎模型中心脏植被的大小增加。在 申请人在基本细菌学实验室中的大师研究，申请人发现了质粒PCF10 重塑粪肠球菌生物膜在粘性表面附属物中产生巨大的刚性结构 生物膜并导致生产含有刚性的粘性生物膜的非附着的生物膜聚集体 结构。对于博士学位申请人希望进行生物医学研究，包括动物建模和人类 血小板。中心假设是生物膜和生物膜聚集体中的刚性结构，通过 三种独特的机制，即多个位点对糖蛋白IB/v/ix产生血栓烷的效果 A2（AIM 1）和PKC用于血小板激活和注射Y155磷酸化都将有助于 增加血栓形成风险，导致感染含质粒菌株的动物的败血症（AIM 2）。 该项目的完成将有助于候选人建立生物医学疾病研究的职业，并通过 对教育的兴趣，候选人将成为进一步招募和培训URM科学家的榜样。