ISS: Exploiting the Space Environment to Dissect the Molecular Basis of Streptococcus pneumoniae (Spn) Cardiotoxicity”

肺炎链球菌(Spn)是一种革兰氏阳性菌，是社区获得性肺炎的主要病因。在严重的社区获得性肺炎期间，Spn进入并对心脏等重要器官造成长期损害。尽管使用了抗生素来治疗肺炎，但其中大量患者仍有患心脏病的风险。目前的研究证实Spn可以感染心脏并在心肌内建立生物膜，导致细胞死亡和肌肉功能障碍。然而，对于允许Spn克服抗生素治疗并对心脏造成损害的关键因素仍有不完全的了解。在这个项目中，心脏组织芯片(CTC)模型将被用于研究Spn感染。空间环境(已被证明会加剧细菌感染)将使研究人员能够清楚地确定在这一过程中发挥作用的重要因素，以确定新的治疗方案。该项目还将为1名研究生、2名本科生和2名高中生提供多学科培训机会。这些本科生将通过UABs范式计划(为研究生和医学院做准备)招募，这是一个暑期计划，面向来自弱势和代表性不足的少数族裔背景的本科生，他们热衷于探索未来作为科学调查员或医疗专业人员的职业潜力。该项目的研究成果将被纳入两门课程的模块，重点是干细胞生物工程和心力衰竭。该项目的目标是利用与空间环境相关的独特现象来创建Spn感染心脏组织的模型，以了解与Spn感染的发生和发展相关的关键分子信号通路，从而导致心脏组织功能障碍。在太空中，多种因素会影响正常的组织和细胞功能，例如促进心脏组织萎缩，使其更容易受到细菌感染。也有充分的证据表明，空间环境，特别是微重力，大大增加了细菌的毒力，降低了对常用抗菌治疗的敏感性。该项目将利用空间环境放大Spn感染的影响，以更有效地确定与促进Spn心脏毒性的关键事件有关的分子变化(基因表达、可溶性因子产生)。阐明发挥作用的分子机制将有助于确定早期干预的治疗靶点，以预防不良心脏事件。该项目的成功完成将证实空间环境引起的组织水平和器官水平的变化加速和加剧细菌感染，并将产生关于以下方面的有价值的信息：(A)Spn感染在地球和太空中的不同；(B)促进毒力增强和生物被膜形成的分子机制；(C)促进太空中抗药性增加的因素；以及(D)确定早期干预的潜在治疗目标，以防止不良心脏事件。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Streptococcus pneumonia (Spn), a Gram-positive bacterium is the leading cause of community-acquired pneumonia. During severe community-acquired pneumonia, Spn enters and causes long-lasting damage in vital organs such as the heart. Despite the use of antibiotics to treat the pneumonia, a large number of these patients are still at risk for heart disease. Current knowledge confirms that Spn can infect the heart and establish biofilms within the heart muscle, resulting in cell death and muscle dysfunction. However, there is still an incomplete understanding of critical factors that allow Spn to overcome treatment with antibiotics and cause damage in the heart. In this project, a Cardiac Tissue Chip (CTC) model will be used to study Spn infections. The space environment (which has been shown to worsen bacterial infections) will enable the researchers to clearly identify important factors that play a role in this process to identify new treatment options. This project will also provide multi-disciplinary training opportunities for 1 graduate student, 2 undergraduate students and 2 high school students. The undergraduate students will be recruited via UABs PARAdiGM program (Preparation for graduate and medical school), a summer program for undergraduates from disadvantaged and underrepresented minority backgrounds who are keen to explore the potential of a future career as a scientific investigator or medical professional. Research outcomes from this project will be incorporated into modules for two courses focused on stem cell bioengineering and heart failure.The goal of this project is to exploit unique phenomena associated with the space environment to create a model of Spn infection of cardiac tissue to gain an understanding of critical molecular signaling pathways associated with the onset and progression of Spn infections that lead to cardiac tissue dysfunction. In space, multiple factors affect normal tissue and cellular function, such as promoting cardiac tissue atrophy making it more susceptible to bacterial infection. There is also sufficient evidence to suggest that the space environment, particularly microgravity, greatly increases bacterial virulence and diminishes susceptibility to commonly used antimicrobial treatments. This project will leverage the space environment to amplify the effects of Spn infection to more effectively identify molecular changes (gene expression, soluble factor production) involved in critical events that promote Spn cardiotoxicity. Elucidation of molecular mechanisms at play will enable identification of therapeutic targets for early intervention to prevent adverse cardiac events. Successful completion of this project will confirm that the tissue-level and organ-level changes engendered by the space environment accelerate and exacerbate bacterial infection and will yield valuable information regarding: (a) how Spn infection of cardiac tissue is different on earth and in space, (b) molecular mechanisms that promote enhanced virulence and biofilm formation, (c) factors that promote increased drug resistance in space, and (d) identification of potential therapeutic targets for early intervention to prevent adverse cardiac events.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.