Our lab is known for uncovering a Nuclear Receptor Super family that includes receptors for steroids, retinoids, and thyroid hormone. These are ligand-dependent transcription factors that function by regulating gene networks. Unexpectedly, this Superfamily contains 48 NRs and is considered the principal molecular entity that encodes and controls body physiology, growth, reproduction, development, neurogenesis, mitochondrial biology and more. Approximately 10–20% of current FDA-approved drugs that have a market value of 30 billion dollars per year target nuclear receptors.
Simply said, metabolism allows organisms to grow, reproduce and sustain life through a series of chemical reactions that convert food into energy. Our lab examines the molecular irregularities associated with metabolism, and how they cause metabolic-related conditions, such as obesity, type 2 diabetes, muscular dystrophy and cancer. The obesity epidemic is the single most challenging medical problem of the modern era.
As one example, our lab discovered the nuclear hormone receptor PPAR-delta which is naturally activated during exercise to burn fat. However, obesity is linked to sedentary behavior and in the absence of fat burning, energy balance is disrupted, resulting in chronic inflammation, increasing risk for fatty liver disease, heart disease, Type 2 Diabetes and cancer. Accordingly, PPAR-delta has become a major therapeutic target site for a class of drugs that can promote fat burning and reverse metabolic disorders. These drugs are often called exercise mimetics because they activate the exercise gene network in skeletal muscle cells that halts weight gain, lowers cholesterol, reduces inflammation and suppress diabetes.
During a meal, insulin is released to rapidly drive sugar and fat into the adipose depot to be stored safely as triglycerides. However, with obesity, the overly stressed fat pad becomes insulin-resistant resulting in sustained serum levels of glucose, long chain fatty acids and insulin. This ‘trifecta’, termed Metabolic Syndrome, is a cluster of conditions increasing risk for heart disease, stroke, fatty liver and type 2 diabetes. While exceptionally hard to treat, using a 500K component screen, we discovered that the hormone FGF1 is able to rapidly regulate blood glucose, even in insulin-resistant mice, and that repeated FGF1 treatment restores insulin sensitivity. FGF1 is a potent weapon to overcome Metabolic Syndrome. Exploring the details of this previously unrecognized pathway may offer new insights for drug discovery.
Circadian rhythms impact almost every aspect of human physiology. Our lab also researches how nuclear receptors modulate gene expression and how they play a major role in regulating the circadian rhythm as it relates to metabolism. We found that reducing the expression of the genes that encode nuclear receptors REV-ERB-alpha and REV-ERB-beta can profoundly disrupt the expression of circadian clock and lipid homeostatic gene networks in mice. This discovery revealed the important roles REV-ERB-alpha and REV-ERB-beta play in maintaining healthy sleeping and eating cycles, hinting at new avenues for treating disorders of both systems, such as jet lag, obesity and diabetes.
Investigating the molecular basis of metabolic diseases presents new opportunities for potentially treating conditions such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH). NAFLD is commonly linked to insulin resistance and is characterized by benign liver fat accumulation, whereas NASH is characterized by inflammation, related to liver damage and fibrosis. We recently sought to understand mechanisms that cause the escalation of NAFLD to NASH and found that the progression can be attributed to antagonistic crosstalk between two regulatory pathways; one is triggered by sterol deficiency and the other by liver cell endoplasmic reticulum stress coupled with a high-fat high-sugar diet. Our findings home in on specific dietary factors involved in switching from NAFLD to NASH and will guide the development of pharmacological treatments for these diseases.
Glycolytic (i.e. anerobic) metabolism is a hallmark of cancer cells, while quiescent cells are powered by oxidative (i.e. fat burning) metabolism. Thus, metabolic switching is key to understanding cancer along with a way to reprogram these metabolic states. In this context, NRs as potent metabolic regulators offer new strategies to address cancers. We study both Pancreatic and Colon Cancer which are both considered to be ‘untreatable.’ Pancreatic cancer is the fifth leading cause of cancer deaths in the United States, with only 8 percent of patients surviving more than five years. Pancreatic cancer is notoriously difficult to detect and as a result patients are typically diagnosed in late stages, once their cancer has already metastasized. Additionally, pancreatic tumors co-opt the body’s natural wound-healing response by hiding behind walls of immune cells and inflammatory molecules, subsisting on the nutrients they require for survival. This unique armament, known as the stromal barrier, makes pancreatic cancers impervious to both chemotherapy and immunotherapy.
Our lab has shown that a specialized synthetic vitamin D therapy can be leveraged to break up the stromal barrier by acting as a molecular “off switch” that sends a message to halt the production of cells comprising the stromal barrier. Targeting the vitamin D receptor offered a unique opportunity to cut off nutritional supply to the tumor and suppress further inflammation, which increased the effectiveness of chemotherapy treatment and reduced tumor volume in mice. Our vitamin D based therapy is supported by Stand UP 2 Cancer, the Lustgarten Foundation, and Merck and is in clinical trials at Dana Farber Cancer and UPENN. Using AI technology, genome wide epigenetic analysis and pancreatic cancer organoids from patients, we have uncovered new ways to develop cutting edge advanced therapies.
Similar to the above we are making major advances on inflammatory bowel disease (IBD) and colorectal cancer (CRC). We recently found that high-fat diets fuel tumor growth in colorectal cancer by upsetting intestinal bile acids and triggering a hormonal signal that allows potentially cancerous cells to thrive. A unique convergence between lifestyle and genetics suggests animals with an APC mutation, which normally acts as a tumor suppressor and is commonly found in humans with colorectal cancer, developed cancer at a faster rate when fed a high-fat diet. We have discovered that the nuclear receptor FXR is a master regulator of intestinal physiology and is “turned off” or suppressed by IBD inflammation as well as by CRC. In both cases, we find that turning intestinal FXR back on reduces inflammation, lowers growth and extends survival of CRC in mice.