Nuclear Receptor Corepressor 1 and 2 and Their Role in Metabolism via Intestinal Actions

Boston University Medical Campus, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT The nuclear receptor corepressor 1 (NCoR1) and it’s paralog, the nuclear receptor corepressor 2 (NCoR2; also the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)) are critical proteins that help maintain metabolic health and normal physiologic function in nearly all tissues where they have been studied. Despite this, much remains unknown about the molecular mechanisms and targets of NCoR1 and SMRT and how they act in a tissue-specific fashion to regulate body weight, glucose levels, and insulin sensitivity – key parts of the pathogenesis of diabetes, obesity, and other metabolic conditions. Although many advances have been made in the treatment of diabetes and obesity, there remain fundamental gaps in our knowledge about these diseases. Advancing our understanding of how NCoR1 and SMRT regulate metabolic pathways has the potential to identify new targets for treating metabolic diseases. This is a five-year research proposal and career development plan focused on the study of the molecular mechanisms of NCoR1 and SMRT in metabolic health, specifically via their actions in the intestine. The aim is to expand our understanding of body weight and glucose regulation by NCoR1 and SMRT, which we hypothesize is in part by actions on key carbohydrate transporters. The candidate is an Assistant Professor of Medicine in the Section of Endocrinology, Diabetes, Nutrition, and Weight Management at Boston University’s Chobanian and Avedisian School of Medicine. The proposed research will be carried out under the mentorship of Dr. Anthony N. Hollenberg, a leader in the field of NCoR1, SMRT and thyroid hormone action who has trained many young investigators. An advisory committee of talented and well-established physician-scientists has been assembled to offer guidance with experimental plans and career development. The School of Medicine has extensive core facilities, resources, and intellectual expertise so is an ideal training environment for the candidate to transition to an independent physician-scientist. This proposal continues upon the preliminary experiments that show the loss of these proteins throughout the intestine leads to a reduction in body weight and lower glucose levels. More specifically, this study aims to determine the functional mechanism by which their loss leads to these outcomes (Aim 1), to identify the pathways regulated and molecular targets of NCoR1 and SMRT in the intestine (Aim 2), and to establish a model of NCoR1 and SMRT knock-out in a human intestinal organoid cell line (Aim 3). These experiments will elucidate the molecular mechanisms and pathways regulated by NCoR1 and SMRT in mice and begin to translate these findings in a human model. The results of these studies will further our understanding of the physiologic underpinnings of body weight and glucose levels and will highlight pathways on which to base future therapies. We expect these experiments will allow us to improve the care of patients with metabolic diseases, first and foremost by giving us an understanding of disease mechanisms.