4351 Natural Science II
University of California Irvine
Irvine, CA 92697
Tel: (949) 824-8573
Fax: (949) 824-4709
Website: Lab Homepage
Hormonal signaling; Functional genomics – Researchers in the Blumberg laboratory study a family of ligand-modulated transcription factors, the nuclear hormone receptors, and their role in development, physiology and disease. Two receptors are particularly relevant to cancer – the retinoic acid receptors, RARs, and the steroid and xenobiotic receptor, SXR.
One long-standing interest in the laboratory concerns the interactions between nuclear receptor and growth factor signaling in important developmental patterning processes. Retinoic acid (RA) and fibroblast growth factors (FGFs) are critical factors that interact to mediate a variety of developmental processes. RA and FGF pathways are mutually inhibitory and this inhibition is important for key developmental processes such as sensory placode formation, neuronal differentiation, somite differentiation, anteroposterior and dorsoventral patterning and the proliferation of stem cells and cancer cells. The Blumberg lab seeks to understand the genetic program and molecular interactions underlying the mutual antagonism between RA and FGF signals in embryonic development and in stem cell differentiation.
A second major interest in the Blumberg laboratory concerns gene-environment interactions and the developmental basis of health and disease. Two receptors are of particular interest in this research, the steroid and xenobiotic receptor, SXR, and the peroxisome proliferator activated receptor gamma (PPARγ). SXR is the key mediator of the body’s response to endobiotics, dietary and xenobiotic chemicals. Differences in SXR underlie some of the known differences between humans and animals and among individuals in their ability to metabolize drugs and chemicals. SXR is also an important mediator of immune function and loss of SXR function leads to widespread inflammation and cancer. Activation of SXR leads to apoptosis of breast cancer cells and may have anti-cancer effects in other tissues.
Obesity and obesity-related disorders such as type 2 diabetes and coronary artery disease have become an epidemic of global proportions. Excessive consumption of calorie-dense food and diminished physical activity (the “Couch Potato model”) are the generally accepted causal factors for obesity. But can environmental factors play a role in exposing preexisting genetic differences or amplifying the effects of diet and excerise? Our “obesogen hypothesis” proposes the existence of environmental chemicals that can perturb lipid homeostasis, adipocyte development and adipose tissue function. We identified organotins as bona fide obesogens that cause adipocyte differentiation in vitro and fat accumulation in vivo. Moreover, prenatal exposure to organotins reprograms metabolism such that affected animals are predisposed to weight gain later in life, despite a normal diet. Understanding the role of these environmental obesogens in regulating fat cell development will provide important insights into a novel contributing factor for obesity.