Saturday, May 18, 2024
5/18/2024
PROJECT SUMMARY Current ulcerative colitis (UC) treatments only alleviate symptoms and maintain remission of UC. Thus, studies to identify new regulatory factors are required. Long noncoding RNAs (lncRNAs) account for a significant proportion of the human genome and have been implicated in the development of chronic and inflammatory diseases. To date, a small number of studies have indicated that lncRNAs play a role in regulating intestinal epithelial barrier integrity, and lncRNA expression has been shown to correlate with disease progression in UC. Yet, the physiological functions of lncRNAs in the pathogenesis of UC remain unknown. Recent studies indicate that lncRNAs can localize to specific organelles and regulate cellular metabolic pathways. However, there is a significant gap in our knowledge of the physiological function of these subcellular lncRNAs in the tissue microenvironment. During my postdoctoral studies in the laboratory of Dr. Kate Fitzgerald at UMass Chan Medical School, I identified a novel transcript of the lncRNA HOXA11os that translocates to the mitochondria in colonic cells. Through direct interactions with proteins associated with the Krebs cycle and complex I of the electron transfer chain, HOXA11os regulates oxidative phosphorylation and ATP production in the distal colon to restrict intestinal inflammation. This study pioneered our understanding of lncRNA function in colonic tissue and provided the first evidence of a lncRNA that localizes to the mitochondria to regulate its activity. The question remains whether additional lncRNAs localize to other organelles and regulate metabolic pathways. Thus, the overall goal of this proposal is to identify and characterize organelle-residing lncRNAs that regulate tissue homeostasis and inflammation through direct regulation of organelle function and metabolic pathways. This proposal is focused on three Research Areas. The first Research Area will focus on identifying endogenous lncRNAs that localize to organelles and the molecular mechanisms regulating their subcellular trafficking and organelle import. The second Research Area will focus on characterizing the precise molecular mechanisms by which organelle-residing lncRNAs regulate protein activity in metabolic pathways associated with UC. The third Research Area will focus on identifying the physiological role of organelle-residing lncRNAs in the onset and progression of UC to target them for treating UC. Together, these studies will identify novel lncRNAs that regulate the function of metabolic organelles to maintain homeostasis and restrict intestinal inflammation. The goals of this proposal are highly relevant to the mission of the NIAID and will enhance our understanding of distinct lncRNA biology in the colon microenvironment. Ultimately, this work will aid in the design and development of therapeutics for the treatment of UC and will potentiate future studies to assess the role of organelle-residing lncRNAs in other inflammatory diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
