PROJECT SUMMARY
Parent award. The initial parent award (P20-GM103625) allowed the University of Arkansas for Medical
Sciences (UAMS) to establish the Center for Microbial Pathogenesis and Host Inflammatory Responses
(CMPHIR). The scientific focus of the CMPHIR is on understanding infectious disease from the perspective of
diverse microbial pathogens and their impact on the host immunological and inflammatory responses influences
the disease process. This theme is based on the premise that understanding the complex interplay between
diverse pathogens and their common human host is a prerequisite to maximizing opportunities to manipulate
one or both sides of this equation in favor of the desired therapeutic outcome. The project is currently in Phase
III (P30-GM145393) with the goal of continuing to support and enhance the critical core facilities to support the
growing number of CMPHIR investigators, continue to provide administrative support to promote further growth
of the CMPHIR and the career development of its investigators, and promote the transition to a self-sustained
Center of Biomedical Research Excellence with the expertise and resources required to address existing and
emerging problems in infectious disease. The current proposal for a Team Science Administrative Supplement
application is directly in line with the goals of the CMPHIR and that it takes a comprehensive, team-based
approach to understanding how the crosstalk between microbiota and the host during antibiotic-induced
dysbiosis, so that new therapeutic strategies can be implemented to maintain host homeostasis and mitigate
disease risk. It is also a direct reflection of the growth of the CMPHIR in that it brings together three investigators
(one current CMPHIR P30 pilot recipient and 2 investigators with various other past COBRE and INBRE ties)
with distinct areas of expertise that can collectively take advantage of their specific strengths and cutting edge
technologies to comprehensively investigate fundamental disease-related processes of highly consequential
bacterial imbalance to an extent that otherwise would not be possible.
Research question. Antibiotic (ABX) use has significantly increased by more than 30% in recent years. Although
ABX fight infections, they also disrupt commensal microbe communities that are crucial for maintaining
homeostasis of various local and distal processes. Microbial imbalance induced by ABX, termed herein as
dysbiosis, has many systemic and long-lasting effects on the host including, but not limited to, increased risk of
vascular pathologies, e.g., solid tumors. Thus, there is a pressing need to reach a deeper understanding of the
crosstalk between microbiota and the host during dysbiosis, so that new therapeutic strategies can be
implemented to maintain host homeostasis and mitigate disease risk. The long-term overarching goal of this
supplement is to initiate a new line of investigation that brings together multiple scientific disciplines for a common
goal of understanding how dysbiosis influences vascular development. The overall objective of this application
is to rigorously and precisely define the molecular composition and cellular functions of small extracellular
vesicles (sEVs) from independent perspectives of an endothelial cell biology and innate immunity in the setting
of angiogenesis. Attaining this objective is critical for future deductive approaches that will guide development of
more effective vascular therapies in patients with acute and chronic dysbiosis. Our central hypothesis is that
independent lipid, nucleic acid and proteomic compositions of dysbiotic sEVs drives homing to vascular beds of
activated vascular endothelial cells and local activation of neutrophils that propel angiogenesis.
Team science approach. The work proposed here relies on the synergy created by a team of investigators,
each of whom brings a unique expertise and/or resource to the project. This truly is a team science approach,
as each of the laboratories bring distinct expertise, skillsets, resources and equipment with virtually no overlap
but shared interest in vascular biology. Our team is a collaboration between a tumor angiogenesis biologist
(Dings), an expert in small RNA and neutrophil biology (Allen), and a renowned expert in lipid metabolism and
lipidomics (Morris) at UAMS and the Arkansas Children’s Nutrition Research Center at the Arkansas Children’s
Hospital Research Institute (ACNC/ACRI). The Dings lab is an expert on ABX-induced dysbiosis and tumor
angiogenesis and will contribute murine models, endothelial cell lines and overall vasculature development
expertise necessary for the proposed studies. The Allen lab brings experience and expertise in extracellular
small RNAs transported by sEVs and lipoproteins, as well as innate immune activity within the vasculature. The
Morris lab is a renowned authority in lipid metabolomics and lipidomics. This supplement will facilitate the
development of a strong collaborative team with complementary skillsets and experimental approaches, thus
allowing for a unique and comprehensive experimental approach that would not otherwise be possible. Teams
will meet at least twice monthly to discuss results and strategize. The data generated will be used for subsequent
grant applications focused on understanding at the molecular and cellular level how dysbiosis-induced sEVs
modulate host vasculature and innate immune responses. Moreover, the data, tools, protocols, and experimental
approach will be applicable to any number of other diseases involving the microbiota. Ultimately, the work
proposed will further enable integration of lipidomics into the parent COBRE and will allow to lay the foundation
of establishing new research infrastructure and resources at the sponsoring institution to be able to support
investigators of other local and national COBRE/INBRE/CTRs in the future.