Dennis James Thiele

Dennis James Thiele
George Barth Geller Professor
Campus mail: C351 LSRC, Durham, NC 27710
Phone: (919) 684-5776

Stress genes in cellular homeostasis and disease

All organisms are exposed to stressful conditions including elevated temperatures, reactive oxygen species and other metabolites generated by normal biochemical reactions, rapid cellular proliferation, infection, inflammation, pharmacological agents or other pathophysiological states. These stressful conditions can lead to protein misfolding and aggregation, disruption of cellular signaling pathways, cellular dysfunction and cell death. Recent studies strongly suggest that the ability to sense and respond to stress signals, through the activation of signal transduction pathways, transcription factors and gene products that function in protein homeostasis is critical for normal growth, development and in the protection against diseases that include cancer, cardiovascular disease and protein folding diseases such as Alzheimer’s, Huntington’s and prion based disease. Furthermore, studies in model systems have established a strong correlation between longevity and the ability to mount robust stress responses for healthy immune systems, normal nutrient sensing and metabolism, protection from infectious disease and the prevention of cardiovascular disease.

Our laboratory explores how organisms sense stress and the mechanisms by which gene expression is activated by Heat Shock Transcription Factors (HSF), a family of central stress-responsive proteins conserved from yeast to humans. Furthermore, we have identified HSF target genes on a genome-wide scale and we are exploring the role these gene products play in protection from disease states such as cardiovascular disease, amyloidoses, prion disease and polyglutamine-based disease. Moreover, we are interested in how distinct stress-responsive pathways communicate. Understanding how HSF is activated, and the role HSF target genes play in cellular homeostasis, is of great importance in the treatment of cardiovascular, neurological and other diseases characterized by stress damage and aberrant protein folding.

Regulation of Copper and Iron acquisition in health and disease

The nutrients copper (Cu) and iron (Fe) serve as essential catalytic co-factors to drive biochemical reactions involved in oxygen transport, neuropeptide hormone maturation, DNA replication, oxidative phosphorylation, blood vessel formation, blood clotting, oxidative stress protection and a variety of other biological processes pivotal to normal growth and development. Our laboratory explores how organisms sense, acquire, distribute and utilize Cu and Fe for these essential processes, and we use yeast, fruit flies, mice and cultured human cells to understand these mechanisms. Given that Cu deficiency causes irreversible developmental and cognitive defects, and Fe deficiency anemia is thought to affect approximately 2 billion people around the globe, understanding how organisms establish homeostatic control of Cu and Fe are of great importance. We study two families of high affinity Cu transporters. The Ctr1 family functions in the delivery of Cu across cell membranes, and mouse knock out studies have established an essential role for Ctr1 in embryonic development and tissue-specific Cu-dependent functions. We are interested in the biochemical function and regulation of Ctr1, and the role of Ctr1 in metazoan development and disease. The Ctr2 family is localized to intracellular membranes and mobilizes intracellular Cu stores. We are exploring the function and mechanism of action of Ctr2, as well as the regulatory mechanisms by which the machinery for extracellular Cu uptake communicates and coordinates with intracellular Cu mobilization.

We have recently discovered a post-transcriptional regulatory process, controlled by Fe deficiency, which drives genome-wide metabolic reprogramming. This coordinated global metabolic reprogramming in response to Fe deficiency is accomplished by targeting specific mRNA molecules for degradation, thereby facilitating the utilization of limited cellular Fe levels. We are investigating the biochemical mechanisms by which specific mRNA molecules are targeted for degradation and the metabolic networks that are reprogrammed as a consequence of Fe deficiency.

Education and Training

  • Rutgers University, Ph.D. 1983