PI: Caroline Genco
Title: The Gonococcal Fur Regulon Link to Pathogenesis
Abstract: Summary Neisseria gonorrhoeae is the etiological agent of the sexually transmitted infection (STI) gonorrhea, a high morbidity disease worldwide with ~ 106 million cases annually. Like many human pathogens this organism must adapt to environments encountered during infection, including low pH and varying oxygen and iron levels. Tight control of gene expression in the gonococcus is mediated in part by the Fur protein, which binds to specific DNA sequences leading to either activation or repression of a repertoire of genes. We recently reported that the gonococcal Fur regulon extends to additional regulatory proteins, which together contribute to gonococcal mechanisms of pathogenesis. We also established that subsets of Fur regulated genes are expressed during natural gonococcal infection in women relative to during growth in vitro. Based collectively on our results we hypothesize that the gonococcal Fur regulon extends to additional regulatory networks that are expressed and regulated in the female genital tract. The studies proposed in this application will define how Fur-mediated regulation is extended through control of additional regulators that are crucial to natural infection. Our analysis will focus on regulatory proteins and sRNAs that are 1) Controlled via Fur (directly or indirectly) and 2) Regulated during natural infection in humans. We term these “gonococcal regulators expressed in vivo” (GREIV). The following Aims are proposed: Aim 1. To define the repertoire of Fur-controlled gonococcal regulatory proteins and sRNAs expressed during natural infection of the female genital tract. Aim 2. To characterize the role of newly identified Fur-controlled GREIV in N. gonorrhoeae interactions with epithelial cells and innate immune cells. Aim 3. To fully define gonococcal global regulatory networks expressed during natural infection of the female genital.
PI: Pam Yelick
Title: Bioengineered Composite Alveolar Bone-tooth Constructs for Tooth Regeneration
Abstract: The coordinated development of craniofacial jaw bones and teeth are the result of a complex interplay between a surprisingly large and growing number of tissues - including blood and vasculature, and nerves – combined with the immune system, and a multitude of growth factor signaling pathways. Although knowledge of signaling pathways resulting in human mineralized tissue development has improved over the past few decades, detailed knowledge and understanding of how to regenerate human mineralized tissues in a functional and timely manner remains elusive – particularly with respect to the craniofacial complex and teeth. Here we propose novel strategies to effectively and coordinately regenerate alveolar jaw bone and tooth tissues, using three dimensional tissue engineering strategies. The objectives of the proposed studies, which build on our prior published reports, are to characterize two potential models for biomimetic three dimensional alveolar bone-tooth constructs: 1) natural decellularized tooth bud extracellular matrix scaffolds; and 2) Gelatin Methacrylate (GelMA) hydrogel scaffolds. Our published expertise in in the field of regenerative dentistry, mineralized tissue development and disease, strong preliminary data, and team of developmental biologists, clinicians and bioengineers supports our ability to accomplish the proposed Aims. We anticipate that the completion of the proposed studies will result in significantly improved knowledge and understanding of new methods to repair craniofacial defects caused by a variety of insults. The significance of the proposed studies and relevance to public health includes the facts that skeletal and craniofacial defects occur in as many as 1 in 700 live births in the United States alone, and that over a quarter of a million Maxillofacial surgeries were performed in 2014, including oral cancer resections. In addition, injuries to the craniofacial complex that include teeth are increasingly common due to accidents and sports injuries, and particularly in the battlefield where they represent up to 20% of injuries. As such, the proposed studies will make a significant contribution towards improved quality of life of both civilian and military populations.