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Your Environment. Your Health.

Cell Biology Group

Nuclear Protein Physiology

Anton M. Jetten, Ph.D.
Anton M. Jetten, Ph.D.
Principal Investigator
Chief, Respiratory Biology Laboratory
Tel (919) 541-2768
Fax (919) 541-4133
jetten@niehs.nih.gov
P.O. Box 12233
Mail Drop D2-01
Research Triangle Park, North Carolina 27709
Delivery Instructions

Research Summary

Our study of retinoic acid receptors led to the discovery of a number of novel transcriptional regulators: several orphan nuclear receptors, nuclear receptor-associated proteins (Project I), and the GLIS proteins (Project II). Subsequent studies revealed that these proteins play critical roles in the regulation of many physiological processes (development, immunity, metabolism), are implicated in several major human pathologies (e.g., asthma, fibrosis, autoimmune disease, diabetes, autism, cancer, metabolic syndrome, cystic kidney disease), provide a link between environment and genome, and offer therapeutic potential to intervene in these illnesses.

 

Project I: Nuclear receptor signaling: Mechanism of Action, Physiological Functions, Roles in Disease, and Potential Therapy.

 

In the last 50 years there has been a substantial increase in the incidence of chronic inflammatory disease that seems to follow the pattern of industrialization and urban living. These incidences include increases in allergic conditions, such as asthma and food allergies, autoimmune disorders (e.g., type 1 diabetes, multiple sclerosis), and metabolic syndrome. It is clear that, in addition to genetic predisposition, environmental risk factors, including endocrine disruptors and diet, play a critical role in these increases. Obesity is a major global health concern and an important theme of the NIH strategic plan  .

 

In the United States alone, 30 percent of the general population is obese and an estimated 66 percent of all adults are overweight. Obesity is a risk factor in several pathologies, including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and asthma. There is increasing evidence for important links between the regulation of metabolism/energy homeostasis and immununological processes (immunometabolism). For example, obesity affects the immune system and promotes inflammation, while immune cells and cytokines can regulate metabolism/energy homeostasis. The RORs and TAK1/TR4 nuclear receptors regulate both immune responses and energy homeostasis/metabolism and as such might be part of the interplay between these two processes.

 

Diagram: Endogenous ligands, endocrine disruptors, and therapeutic drugs going to Nuclear receptors ROR-alpha, ROR-gamma, and TAK1 going to immune responses, as well as energy homeostatsis, metabolism, and stress defense. Both go into Inflammatory disease, autoimmune disease, asthma, metabolic synrome, obesity, diabetes II and oxidative stress.
RORs and TAK1 nuclear receptors play an important role in the interplay between immunological and metabolic processes, mediate environment/genome interactions, and function as potential therapeutic targets.

 

Project II: GLIS Protein Signaling: Mechanism of Action, Physiological Functions, Roles in Disease, and Therapeutic Strategies

 

About 12 percent of the U.S. population suffers from some form of chronic kidney disease, while 10 percent of U.S. adults have type 2 diabetes today. Due to the dramatic increase in obesity, type 2 diabetes is expected to rise over the next 40 years to as many as one in three adults. Worldwide 250 million suffer from type 2 diabetes. Type 1 diabetes increased almost two-fold over a 25-year period in many parts of the U.S. and Europe. The current annual cost related to diabetes is estimated at $174 billion. The GLI-Similar (GLIS) proteins play a critical role in the regulation of pancreas development, insulin expression, and the maintenance of kidney functions and are implicated in inflammation, fibrosis, diabetes, cancer, and cystic kidney disease. GLIS proteins might provide novel therapeutic targets for these diseases.

 

Diagram: Endogenous ligands, endocrine disruptors, and therapeutic drugs going to GLIS2 and GLIS3, which go into inflammation, epithelial-mesenchymal transition, which goes into nephronophthsis. GLIS2 and 3 also go into Planar cell plarity, pancreatic beta-cell generation, insulin expression, T3/T4 metabolism, which go into diabetes, polycystic kidney disease, hypothyroidism, glaucoma, hepatic fibrosis, osteopenia, and cancer.
Glis1-3 proteins function as key regulators of pancreatic beta cell development, renal functions and thyroid hormone metabolism, provide a link between environment and genome, and serve as potential therapeutic targets.

 

Major areas of research:

 

  • To analyze the role of the ROR and TAK1 nuclear receptor signaling pathways in innate and adaptive immune responses in the lung
  • To establish the role of the ROR and TAK1 signaling pathways in oxidative stress and lung cancer
  • To determine the role of the ROR and TAK1 signaling pathways in metabolic syndrome in relation to immune responses
  • To establish the role of GLIS signaling in pancreatic development and diabetes
  • To determine the role of GLIS signaling in the maintenance of renal functions and cystic renal disease

 

Current projects:

 

 

Anton M. Jetten, Ph.D., Head of the Cell Biology Group and Chief of the Laboratory of Respiratory Biology, obtained his Ph.D. from the University of Nijmegen, The Netherlands, and completed postdoctoral studies at the Massachusetts Institute of Technology. He has published over 250 peer-reviewed journal articles and book chapters.

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