Project Summary/Abstract Increasing our knowledge of the human-associated as-yet-uncultivated bacteria is essential in understanding their potential role in human diseases. The TM7 phylum is one such group of bacteria. Despite its ubiquitous presence in the environment and in human body sites as well as its potential implication in periodontitis, no cultivable representatives of the TM7 phylum have been isolated until very recently. Furthermore, TM7 belongs to the newly described Candidate Phyla Radiation (CPR) bacteria, which comprise >15% (>35 phyla) of the entire bacterial domain and lack an isolated representative. Remarkably, CPR organisms share unique biology that does not exist in the rest of the bacterial domain, which include but not limited to ultra-small cell size (200-500nm) and reduced genome (<1Mb) that has highly restricted metabolic capabilities. Our lab isolated the first human oral TM7 species (TM7x) as an obligate epibiotic parasite that lives on the surface of its host bacterium XH001 (an oral Actinomyces odontolyticus strain). Using TM7x/XH001 as a model system, this proposal seeks to fulfill three fundamental knowledge gaps: (1) What are the specific molecular mechanisms that govern the interaction between TM7x and its host bacteria? (2) Do the same rules and mechanisms apply to all TM7 members? (3) What is the role of TM7 in human mucosal inflammatory diseases? The ultimate goal is to unravel the secret lifestyle of TM7 and other CPR bacteria, and truly grasp their impact on human diseases and the environment. Dr. Bor has spent his postdoctoral research studies characterizing the physiological and phenotypic behaviors of TM7x/XH001 interaction and therefore, mechanistic and pathogenic studies of the TM7 bacteria is a logical extension of his research. The proposed K99/R00 research is designed to supplement Dr. Bor's prior research experiences and to train him in required technical and intellectual skills to become an independent investigator. Dr. Bor will be trained at one of the leading research institutes, UCLA. His primary mentor, Dr. Shi, and co-mentors, Dr. He, Dr. McLean and Dr. Dewhirst are well-established, capable individuals who are dedicated to pushing the boundaries of dental research. After the mentored phase of this K99, Dr. Bor's career goal is to become a tenure-track faculty member at a leading academic research institute, where he can further develop his research program on CPR bacteria while mentoring and educating students. Dr. Bor's proposed work will provide key insights into the physiology and pathogenesis of this unique group of host-associated bacteria and may contribute to the development of novel therapeutic tools for treating periodontitis.