Hernandez-Kapila Lab

Current NIH Funded Projects in the Kapila Lab:

NIH R01CA269950: Oral Microbiome and Inflammatory Status in Antimicrobially Treated Oral Cancer Patients

The incidence of oral squamous cell carcinoma (OSCC), the most common type of head and neck cancer, continues to rise among numerous demographic groups in the US, yet its 5-year survival rate has not improved for several decades. Despite advances in targeted therapy, immunotherapy and other novel adjuvant regimens, patients with locoregionally advanced and recurrent/metastatic disease continue to have extremely poor outcomes, underscoring the need for more effective treatments for OSCC, which often goes undiagnosed until it has reached late stages. Primary risk factors for OSCC include tobacco use, alcohol consumption, and for oropharyngeal cancers, HPV infection, but cancer incidence is influenced by additional elements such as anatomic site, patient demographics, and likely the individual’s oral microbiome. Given that cases of OSCC are increasing despite targeted head and neck cancer prevention efforts in the US such as smoking cessation and HPV vaccination, there is a strong rationale for exploring other modifiable risk factors that, together with new therapies, can improve outcomes for patients with OSCC as well as other aggressive head and neck cancers. The oral microbiome is a complex and dynamic community of commensal organisms that can become imbalanced (“dysbiotic”) in response to dietary intake, tobacco and alcohol use, and poor dental hygiene. Dysbiosis can pre-dispose an individual to oral disease, including cancer, by enriching for bacterial pathogens that promote carcinogenesis, secrete carcinogenic compounds, and promote chronic inflammation. Thus, reversing oral dysbiosis is a promising approach for protecting against tumorigenesis. The food additive nisin, which is bactericidal against a broad range of pathogens, has been shown to restore oral microbiome diversity, suppress inflammation, and stimulate anti-tumor cellular responses in vitro and in a polymicrobial mouse model of oral cancer, while maintaining its well-established safety profile. However, the potential clinical benefit of nisin for treating OSCC in humans has not been investigated. Here, we propose a Phase I/IIa trial to establish the tolerability and feasibility of administering nisin to OSCC patients who represent high-risk populations. In parallel, we will perform mechanistic studies of nisin and its effects on oral microbiome community structure, inflammasome expression, and anti-cancer cellular responses of the study participants. We will also analyze the emergence of nisin resistance among key oral bacteria, which could provide insight into circumventing nisin resistance in other clinical contexts. We hypothesize that nisin will be well-tolerated among OSCC patients and will counter dysbiosis by inhibiting bacterial pathogen growth and promoting an anti-tumorigenic environment via immunomodulation and anti-cancer cell activity. Our long-term goals are to validate nisin as a promising candidate for OSCC treatment and demonstrate that oral dysbiosis is a major driver of tumorigenesis in humans that can be manipulated, thus highlighting the important yet mostly unrecognized protective role that antimicrobials can exert against cancer in humans.

NIH R01DE025225: Treponema–Host Cell and Tissue Interactions

ABSTRACT The goal of this research is to characterize the role of Treponema denticola surface proteins in interaction of this human oral spirochete with host tissue, thereby gaining insight into mechanisms by which T. denticola contributes to initiation and progression of periodontal disease. We focus on analysis of T. denticola protein complexes that directly affect cells isolated from tissue comprising the periodontal ligament (PDL) that comprises the junction between the tooth and the alveolar bone of the tooth socket: specifically the PrtP lipoprotein protease complex (dentilisin) and the oligomeric Msp protein. Our overall hypothesis is that dentilisin and Msp are major contributors to T. denticola cytopathic behavior in periodontal disease, In this context we will examine specific domains of dentilisin and Msp, as well as the T. denticola lipooligosaccharide component of the outer membrane. To characterize their specific roles in microbe-host interactions, our approach is to utilize purified native and recombinant proteins as well as isogenic T. denticola strains carrying defined mutations in individual components of these outer membrane complexes. We will first extend our ongoing studies characterizing dentilisin and Msp assembly in the Td outer membrane. Then, to further studies of host responses to challenge by Td and its specific components, we will then characterize in a cell model T. denticola-induced dysregulation of TLR/MyD88 and Integrin/FAK signaling mechanisms and consequences for the cytoskeleton as well as expression and activity of matrix metalloproteinases. We will determine the extent to and the mechanisms by which specific T. denticola components contribute to tissue destruction in a mouse model of periodontal disease. Finally, we will test the ability of the the antimicrobial peptide nisin to modulate T. denticola-induced dysbiotic signaling in both the cell and animal models. Our research team is uniquely positioned to conduct these studies, with combined expertise in spirochete molecular biology, extracellular matrix biology and cytopathology of inflammatory diseases. Completion of this project will contribute to both basic knowledge of spirochete molecular biology and to understanding of microbe-host interactions in chronic infections such as periodontal diseases.

K12 training grant K12 DE027830 UCLA Dental Specialty PhD Program

PROJECT SUMMARY Established in 2018, the overarching goal of the University of California – Los Angeles (UCLA) Dental Specialty PhD Program (DSPP) within the UCLA School of Dentistry (SOD) is to promote the research career development of highly productive, early-career dentist-scientists and to facilitate their transition to independent investigators capable of addressing complex challenges within the dental profession and of advancing dental medicine. The UCLA SOD aspires to transform dental education and research by equipping trainees with experiences that prepare them to be critical thinkers, effective communicators, and compassionate, skilled clinicians capable of delivering patient-centered care in a rapidly evolving health care environment. To this end, the UCLA DSPP successfully recruited and retained two outstanding DSPP Scholars in the prior funding period who have made notable contributions in research related to oral health, one of which is female. To support the UCLA DSPP, the UCLA SOD has established outstanding postgraduate dental training programs that include seven Graduate Medical Education (GME)-supported dental specialty residency programs. The proposed K12 research training includes both PhD research and clinical specialty-oriented research guided by primary research mentors and clinical specialty mentors, respectively. The DSPP Scholars will complete a 3-year clinical specialty training block funded by the GME program followed by a 4.5-year PhD training block funded by the K12 award. Integration of the clinical specialty training and PhD research will be ensured through careful construction of cohesive mentorship teams, sustained clinical effort during the PhD program, coordinated input and guidance on selection of the research focus, inclusion of a critical authentic task, continual progress monitoring, and an established conflict resolution plan. Efforts will be made to achieve diversity of representation among DSPP Scholars and to recruit candidates from historically marginalized communities, including candidates from within the UCLA SOD and from the Texas A&M University College of Dentistry. The UCLA DSPP will provide effective, evidence-based pedagogy, providing all DSPP Scholars an equitable and inclusive learning experience. Finally, Scholars will enter the transition year supported by UCLA SOD to conduct postdoctoral research to facilitate their transition to an independent research career. In the current renewal, the UCLA DSPP seeks to advance ongoing efforts to increase the critical mass of dental school faculty who contribute to both clinical and scientific excellence, ensure diverse representation among future dentist-scientists, and construct collaborative networks involving clinician-scientists equipped with unique skills to address patient-oriented challenges and to transform the future of dentistry.