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.

本研究补充材料旨在促进健康相关研究的多样性， 申请人的项目，这是研究父R35补助金的延伸。申请人是海地裔美国人 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，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的重点是这些信号步骤，以及它们的相互作用如何介导血小板 activation.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，我们的团队对血小板信号传导领域做出了重要贡献。R35的目标是 鉴定调节主要信号传导途径的新型信号传导分子，表征新型信号传导途径 从相同的信号分子发出，并了解不同的酪氨酸激酶 血小板中的通路。补助金的研究设计遵循构成 父母补助金，并将重点研究发现新的信号机制提供的结构 在细菌生物膜内，可以增加血小板活化。肠球菌败血症，主要由 由E.粪肠球菌，可能很难用抗生素治疗，如果感染是 30天内没有解决。该致死率明显高于S。金葡菌，以及增加的基础 死亡率未知。不是所有的E。粪便血流感染导致败血症，这表明可能存在 菌株间变异E.粪菌菌株的范围从胃肠道的普遍存在的寄生虫， 多重耐药医院病原体。移动的遗传因子在转化中起着重要作用 阿格萨尔湖粪肠球菌转化为院内多药耐药（MDR）机会致病菌。信息素 应答质粒可存在于>60%的特征性致病性分离株中，并且与 心内膜炎兔模型中心脏赘生物的大小增加，其机制未知。期间 在基础细菌学实验室的硕士研究中，申请人发现了质粒pCF 10 改造E.粪便生物膜在粘性表面附着的 生物膜，并导致产生含有粘性生物膜的非附着生物膜聚集体， 结构.对于博士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以下方式激活血小板 三种独特的机制，糖蛋白Ib/V/IX上多个位点的牵引作用产生血栓烷 A2（Aim 1）和PKC β 2的血小板活化和Y155磷酸化的炎症都将有助于 增加血栓形成风险，导致感染含质粒菌株的动物出现败血症（目的2）。 该项目的完成将有助于候选人建立在生物医学疾病研究的职业生涯，并与 候选人对教育感兴趣，将成为进一步招聘和培训URM科学家的榜样。