Novel signaling molecules regulating platelet activation

本研究副刊旨在促进与健康相关的研究的多样性，旨在支持 申请者的项目，是研究家长R35资助的延伸。申请人是海地裔美国人。 公民和黑人代表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，它们在包括炎症在内的其他疾病状态中发挥作用， 癌症和动脉粥样硬化。R35侧重于这些信号步骤以及它们如何相互作用来调节血小板 激活。在过去的两年里，了解信令网络及其监管一直是我的研究重点 几十年来，我们的团队在血小板信号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信号分子，表征新的信号通路 来自相同的信号分子，了解不同酪氨酸激酶的差异 血小板中的通路。补充补助金的研究设计遵循构成 父母拨款，并将专注于研究发现结构提供的新信号机制 在细菌生物膜内，可以增加血小板的活性。肠球菌性败血症，主要由 由粪肠球菌感染，可能很难用抗生素治疗，如果感染是 在30天内没有解决。这种致死率明显高于金黄色葡萄球菌，并在此基础上增加 死亡人数不得而知。并非所有粪肠球菌的血流感染都会导致败血症，这表明可能存在 菌株对菌株的变异。粪肠球菌的范围从无处不在的胃肠道共生菌到 多药耐药院内病原菌。可移动的遗传元素在转化过程中起着重要作用 粪肠球菌进入医院多药耐药(MDR)条件致病菌。信息素 反应质粒可存在于60%的特征致病菌株中，并与 心内膜炎兔模型心脏赘生物大小增加的机制未知。在.期间 申请人在基础细菌学实验室攻读硕士学位时，发现了质粒pCF10 重组粪肠球菌生物膜在粘性表面附着的致密堆积刚性结构 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 结构。对于博士学位，申请人希望从事生物医学研究，包括动物建模和人体研究 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，多个位点对糖蛋白Ib/V/IX产生血栓素的拖拽作用 A2(AIM 1)和用于激活血小板的蛋白激酶C和用于炎症的Y155磷酸化都将有助于 增加血栓风险，导致感染含有质粒菌株的动物出现败血症(目标2)。 该项目的完成将有助于应聘者在生物医学疾病研究领域建立职业生涯，并拥有 如果您对教育感兴趣，该候选人将成为进一步招募和培训URM科学家的榜样。

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.