PROJECT SUMMARY/ABSTRACT
This proposal comprises a three-year research and career development program for Rachel Niec, MD, PhD to
achieve independence as an investigator at the intersection of immunology and intestinal epithelial biology. Dr.
Niec completed her doctoral training in immunology at Sloan Kettering Institute and Internal Medicine Residency
and Gastroenterology Fellowship at Weill Cornell Medical College. The research and career development
activities will occur at Rockefeller University. Dr. Niec will engage in career development activities including
didactics, workshops in grant writing and lab management, acquisition of technical skills and scientific expertise,
conference presentations, and a comprehensive mentorship program through her dedicated mentoring team.
Dr. Niec has a strong background in cell biology and, over the course of this K08 award at the Rockefeller
University, aims to expand her skills in advanced microscopy, transcriptomics and stem cell (SC) biology to study
how features of the intestinal SC (ISC) niche interpret diverse cues to direct SC activity in health and in disease.
Inflammatory bowel diseases (IBD) are inflammatory conditions focused within the intestinal epithelium and
driven by genetic, environmental, and microbial factors. Intestinal epithelial maintenance is dependent on ISC
which in turn rely on their niche for local signals to direct their activity. While many niche factors emanate from
local sources, intestinal epithelial tissues is subject to systemic changes suggesting vascular features may
regulate ISC activity. While lymphatics abnormalities have long been appreciated as a feature of IBD, the
vascular features of the intestinal niche that control ISC behavior are unknown. The central hypothesis is
vasculature is a key regulator of ISC function, through direct signaling between vasculature, ISC and other niche
cells. Two specific aims are proposed: (1) Define the contribution of lymphatic capillaries to the cellular network
comprising the intestinal stem cell niche; (2) Determine the impact of lymphatic derived Reln and lymphatic:stem
cell interactions on ISC maintenance and function. These aims will be addressed using tissue clearing and
advanced 3D imaging, established and newly developed single cell and spatial resolution transcriptomics, and
novel in vitro coculture and in vivo molecular genetic approaches. The significance of this proposal lies in its
relevance to fundamental mechanism of epithelial maintenance and regeneration and to pathogenesis of IBD.
The proposal is innovative in the combination of advanced methods in imaging and transcriptomics and their
application to SC niche biology and intestinal inflammation. Long-term, Dr. Niec aims to apply the expertise
gained to identify environmental and inflammatory signals that maintain and regulate the intestinal SC niche in
homeostasis and disease to improve prevention and treatment of IBD.