I am applying for a Mentored Research Scientist Development Award from NIDDK to facilitate my transition to an independent investigator studying host-microbe interactions and metabolic diseases. I am an experimental biologist with extensive training examining host-microbe interactions in health and disease. My recent publication under the mentorship of Dr. Eugene B. Chang identified that gut microbes exhibit diurnal patterns that are tightly aligned with host circadian rhythm. Diet-induced microbial dysbiosis disrupts this interaction, leading to development of obesity. My proposal will focus on filling gaps in knowledge to define the underlying mechanisms that drive daily microbial oscillations. I will examine the interplay between innate immune functions and diurnal patterns of intestinal microbes located within the distal small intestine. My long- term goal is to gain insights into the bi-directional relationship between host and microbe that leads to the resetting of the localized intestinal clock. I have designed the career development benchmarks of this K01 award to expand my knowledge base and gain expertise in the areas of molecular circadian biology, microbiology, and innate immune function. I have gathered a mentorship team to oversee my proposed work, which will be lead by Dr. Eugene B. Chang. I will be co-mentored by Drs. Brian J. Prendergast (UChicago), Eve Van Cauter (UChicago), and Mitchell L. Sogin (Marine Biological Laboratory). The mentorship team has participated in designing the career training program and approved the proposed research timeline, coursework, skill development workshops, and manuscript/grant submission timeline. They will be involved throughout the award to provide guidance and oversight for research design and methods, troubleshooting, scientific direction and evaluation, as well as preparation of manuscripts, grants, and presentations. I will receive additional support via my department and division chairs as well as a group of consultants, including Drs. Jennifer Evans (Marquette University ? molecular circadian biology), Aaron Dinner (University of Chicago ? statistical approaches for circadian time series analysis), A. Murat Eren (University of Chicago ? Microbial community analysis), and Dean P. Jones (Emory University ? metabolomics). The research environment at the University of Chicago is ideal to accomplish my proposed research aims and provides all necessary tools to successfully complete my goals. I will examine the underlying mechanisms that drive daily oscillations in gut microbes, specifically the interplay between innate immune functions and distal small intestinal microbes. I observed that oscillations of gut microbes are synchronized with host diurnal expression patterns of genes involved in antimicrobial peptide synthesis, specifically regenerating islet-derived 3 gamma (Reg3?). How diurnal patterns in Reg3? expression aid in maintenance of normal gut microbial oscillations and what the implications are for host metabolic health remain unexplored. The long-term goal is to determine how oscillations of gut microbes influence diurnal dynamics of intestinal host factors that aid in maintenance of a host-microbe symbiotic relationship. This knowledge could lead to development of new strategies to prevent and treat diet-induced obesity.
In this proposal, I will examine how the local, reciprocating relationship between gut microbial community structure and function and mucosal innate immunity leads to diurnal variations in gut microbes that are critically important and synchronized with host circadian rhythm and metabolic outcome. I will test whether desynchronization of these local intestinal interactions can result in circadian rhythm disruption, which leads to obesity.
|Frazier, Katya; Leone, Vanessa (2017) Keeping Time in a Relay Race for Fat. Cell Host Microbe 22:425-427|