Piezo1- Mediated Type H Vessel Formation in Periodontitis

Project Summary/Abstract Periodontitis is defined as an inflammatory bone lytic disease of which onset and progression is associated with the host immune responses to the dysbiosis of periodontal microbiome. Type H vessels characterized by the cell surface markers, CD31 and endomucin (EMCN), have been found in bone tissue as microvascular structures that is specialized in the induction and maintenance of osteogenesis. Piezo1, a mechanosensitive receptor expressed on endothelial cells (ECs) play relevant regulatory roles in development, growth and function of ECs. The preliminary results showed that the number of Type H vessels in alveolar bone diminished in periodontitis compared to that in periodontally healthy alveolar bone, and that activation of Piezo1 expressed on EC can promote the polarization of ECs toward Type H phenotypes. The EMCN expressed on ECs was reported to interrupt the leukocyte’s trans-EC migration. Based on these lines of evidence and preliminary results, it is hypothesized that activation of Piezo1 expressed in vascular ECs induces polarization of type H vessels which, in turn, down-regulate the infiltration of osteoclast precursors from blood circulation to the bone surface of alveolar bone in periodontitis. This hypothesis will be tested by the following two Specific Aims: Aim 1) To demonstrate that the stimulation of Piezo1 expressed on vascular ECs can polarize them towards type H vessels. Aim 2) To determine the role of Piezo1 expressed on ECs in the type-H vessel formation using a mouse periodontitis. Major four training goals in the career development plan include: 1) Gain and improve expertise in basic scientific methods associated with osteo-vascular biology, osteoimmunology and periodontology, 2) Obtain skills in management and analyses of datasets, 3) Acquire technical methods to conduct proposed K08 research strategy, and 4) Develop competencies required to lead a research program, including participation of grant writing course and workshop. Mentor, Dr. Han, and co-mentor, Dr. Kawai, Dr. Du and Dr. Crane who are experienced in the proposed study addressing the periodontal osteoimmunology, microfluidics or type H vascular biology, as well as mentoring of postdoctoral fellows and junior faculties for their career development in the academic research fields, will be committed to support the candidate’s career development, along with consultation committees composed of 3 expert researchers in the fields of pathological immune dysregulation related to the leukocyte migration, 3D transparent tissue histology, and Piezo1-mediated mechanosensory system, respectively. All required equipment, devices, protocols and materials are available in the laboratories of mentors and consultants. The candidate is given a desk and laboratory space in Center for Collaborative Research (CCR) which is the largest biomedical research building in South Florida, equipped with a variety of cutting-edge equipment in the core facilities, all of which are available for the candidate’s research project. The successful completion of this potentially paradigm shifting project in periodontal research is expected to form the foundation for a future RO1 grant application.