Growth Factors, Cytokine Interactions in Gastrointestinal Disease, Stem Cells and Obesity
The Lund Lab has three major funded research projects focused on intestinal stem cells, colorectal cancer and inflammatory bowel diseases.
1-R01-AG041198-01 (PI Lund), NIH/NIA , Aging intestinal stem cells and insulin/IGF system
This grant aims to establish the impact of aging on the functional and molecular phenotype of intestinal epithelial stem cells (IESC) and to define the roles of the insulin receptor (IR) and the insulin-like growth factor 1 receptor (IGFR1), in stem cell aging. A major goal is to compare gene expression profiles and growth potential in culture of normal IESC and regenerating IESC after injury by radiation in young and aged mice. The study uses using reporter mice to isolate IESC (Sox9-EGFPLow; Lgr5-EGFP and Bmi-YFP), progenitors (Sox9-EGFPSublow), enteroendocrine cells (Sox9-EGFPHigh) which may contain an alternate IESC population, and differentiated lineages (Sox9-EGFPNegative). In addition we wish to test whether IESC acquire genetic mutations with aging that impact their function. This will use novel single cell genomics and transcriptomic approaches.a It is well established that excessive IGF1R signaling promotes organismal aging while preserved IR signaling (as occurs in lean individuals or is compromised in obesity) protects against aging. IESC reporter mice with specific deletion of either IGF1R or IR in IESC and other intestinal epithelial cells will test a hypothesis that excessive IGF1R signaling promotes stem cell and intestinal epithelial aging and impairs long-term regenerative capabilities due to stem cell exhaustion while IR protects against these processes. The impact of these studies is that we will be able to guide interventions to preserve IESC and intestinal epithelial function over aging and define biomarkers that can be used to detect aberrant IESC aging in translational studies.
R01-DK040247-20 (PI Lund): Intestinal Adaptation-Role of Hormones and Growth Factors
This grant uses IESC reporter models and IGF1R, IR mutants to define the roles of IGF1R versus IR in normal renewal and differentiation of the intestinal epithelium and in tumor promoting roles of obesity or insulin formulations commonly used in diabetes.
R01-DK047769-12 (PI Lund): Growth Factors and Inflammatory Bowel Disease
The project focuses on roles of suppressors of cytokine signaling (SOCS) as novel inhibitors of inflammation associated intestinal cancer or fibrosis. Activatable molecular probes and optical imaging is used for early tumor detection. In addition, new areas of research aim to define changes in different mesenchymal cell populations (fibroblasts, myofibroblasts, smooth muscle cells) over the course of normal wound healing or fibrosis. Fibrosis is a currently incurable and poorly understood complication of Crohn’s disease, which results in need for surgery in up to 65% of individuals, with high recurrence and no effective therapies. We have developed reporter mice that permit isolation of cells that are altered to collagen expressing fiborogenic phenotype (Collagen promoter-GFP mice), and mice that permit separation of fibroblasts, myofibroblasts and smooth muscle cells based on sorting for an alpha-smooth muscle actin (αSMA)-dsRed reporter. We will define genetic, transcriptomic and functional differences in these distinct mesenchymal sub-types, including evaluation of potential epigenetic changes that may promote fibrosis.