Chemical Physiology

Chairman's Overview

Benjamin F. Cravatt III, Ph.D., Chairman

Photo of Benjamin Cravatt
The Chemical Physiology Department aims to bring together researchers dedicated to developing and utilizing cutting-edge chemical technologies to address biological problems of exceptional complexity and medical relevance. The success of genome sequencing projects has propelled 21st century biologists and chemists into an era where focus has shifted from the discovery of new genes to the functional characterization of gene products. Indeed, of the more than 20,000 genes found in the human genome, at least half are lacking functional annotation. This finding underscores how little we still understand about the molecular basis of life and its disorders, while at the same time highlighting the tremendous opportunity that awaits post-genomic researchers interested in advancing new methods to characterize gene and protein function on a global scale.

Recent discoveries made by researchers in our department are highlighted below.

Marty Fedor is studying the mechanisms of RNA catalysis, which controls many important cellular processes, including gene expression and mRNA stability. Her group has used innovative biophysical methods to overturn generally accepted views for how RNA molecules cleave phosphodiester bonds.

Natasha Kralli has discovered a network of protein regulators of nuclear receptors and is elucidating their roles in controlling mitochondrial biogenesis using a combination of chemical and genetic technologies.

Katja Lamia has discovered that circadian clock timing is set by metabolic signals via the AMP-activated protein kinase, and that clocks in turn regulate mammalian cellular and organismal metabolism. Her lab is studying the energy-regulated circadian transcriptional repressors known as cryptochromes, and their roles in glucose, lipid and drug metabolism.

Jeanne Loring has applied large-scale profiling technologies to map molecular signatures that define the pluripotency of human embryonic stem cells, which point to key genes and proteins that can be targeted to control the differentiation potential of these cells.

Kerri Mowen has discovered that the unusual post-translational modification, arginine methylation, plays an important role in regulating the expression of cytokines in T cells. These studies may lead to the identification of new therapeutic targets to treat diseases that display excessive cytokine signaling, such as arthritis.

In his own group and as Director of the Consortium for Functional Glycomics, Jim Paulson had developed innovative technologies for characterizing and controlling carbohydrate-protein interactions on a global scale, in particular interactions that involve the siglec family of sialic acid-binding proteins. These proteins play critical roles in the immune system and the advancement of new methods to control their signaling could lead to new strategies to treat immune system disorders.

Michael Petrascheck's group uses small molecules that extend lifespan as tools to study the molecular connection between aging and age-related disease. In particular, they ask whether molecules that extend lifespan can be used to treat age-related disease and whether the disruption of longevity pathways by age-related diseases is part of the pathology of the disease.

In his own group and as Director of TSRI’s Molecular Screening Center, Hugh Rosen has created powerful new chemical probes to selectively perturb receptors in the sphingosine 1-phosphate (S1P) signaling network. These probes have revealed important functions for S1P receptors in immunosuppression, inflammation, and maintenance of vascular integrity.

Enrique Saez has determined that the liver X receptor (LXR), which is involved in maintaining cholesterol and triglyceride homeostasis, also is activated by the sugar glucose. LXR thus serves as a key node for crosstalk between lipid and sugar metabolic pathways and could play a role in both diabetic and atherosclerotic syndromes.

Supriya Srinivasan has identified the major genetic pathways by which the neurotransmitter serotonin controls a fundamental neuroendocrine axis to match food intake, fat content and energy expenditure, with environmental demands. She uses C. elegans as a model system to discover and couple molecular mechanisms to specific phenotypes and neuroendocrine networks of energy balance.

John Yates has continued to serve as a pioneer in the development and application of advanced mass spectrometry-based proteomics methods for large-scale analysis of proteins in biological systems. In particular, they have used proteomics to identify proteins that are controlled by insulin, greatly expanding our knowledge of the pathways that are regulated by and feedback on this key hormonal signal.

Our group has used active site-directed chemical probes to broadly profile enzyme classes in complex biological systems, leading to the discovery of novel enzymes that regulate key lipid signaling molecules in the brain and enzymatic pathways that are dysregulated in human cancer cells.