Michael Jarstfer, PhD
Synthetic chemistry, molecular biology, and combinatorial chemistry techniques are used to investigate the ribonucleoprotein telomerase, which plays a pivotal role in tumorgenesis.
Research in the Jarstfer Lab employs diverse techniques to study pathways critical for human health and currently focus on telomere biology. They are investigating the association between telomere function and cellular immortality, cardiovascular disease and cancer and are investigating the structure function relationship of telomerase. They are also interested in the pharmacological control of complex social behavior such as social approach and social memory.
Structure, Function, and Regulation of Telomerase
A primary of area of research in the Jarstfer lab is the structure and function of telomerase. Telomerase is an enzyme necessary with cellular immortality with good (long life) and bad (cancer) consequences of its activity. Telomerase has a very specific and peculiar activity: it extends only one strand of DNA found at the 3’ end of each chromosome. The ends of chromosomes are called telomeres and telomere function is essential for cellular proliferation. As humans age, telomeric DNA erodes leading to dysfunctional telomeres. In turn, dysfunctional telomeres prevent cellular proliferation and in vivo this can affect everything from wound healing, immune system vitality, and vascular health. Thus, elevated telomerase activity could arguable serve as a cellular fountain of youth. On the flip side, the vast majority of cancer cells types depend on telomerase for their survival, making it a potentially universal anticancer drug target. Jarstfer’s group has investigated telomerase structure by electron microscopy (Biochemistry, 2006, 45, 9624-31) and chemical structural probes (EMBO J. 2006 25, 3156-66). They have also investigated telomerase regulation and found that the heat shock proteins hsp90 maintains human telomerase in a stable state (J Biol Chem 2006 281, 19840-8) and found that human telomerase is regulated by caspases, which are the enzyme that initiate and execute programmed cell death (Biochemistry 2011 Epub ahead of print). Currently, they are testing a 3D model of telomerase they generated in collaboration with the lab of Nikolay Dokholyan, determining the role of caspase cleavage of human telomerase on cellular biology, and developing new techniques to study telomerase structure in cells.
Targeting Telomere Maintenance for Anticancer Drug Discovery
Telomere function is an absolute requirement of cancer cells and telomere dysfunction affects cancer cells differently than normal cells: cancer cells with dysfunctional telomere generally undergo apoptosis. Jarstfer’s groups seeks to take advantage of this difference to identify reagents that prevent proper telomere maintenance. They have developed screens for telomerase assemblage (Anal Biochem, 2006, 353, 75-82), identified regions of human telomerase that are good targets to disrupt telomerase assemblage (Biochemistry, 2004, 43, 334-43), and have identified small molecules that prevent proper telomerase assemblage (Bioorg Med Chem Lett, 2004, 14, 3467-71). The group has also generated molecules that block the interaction of telomere-binding proteins with the single-stranded region of the telomere (Bioorg Med Chem, 2009, 17, 2030-7). Currently, they are developing a platform for the targeted destruction of cellular human telomerase.
The Role of Telomerase and Telomere Maintenance in Metabolic Syndrome
Jarstfer’s group has determined that telomerase is a target of reactive oxygen species (Bioorg Med Chem. in press). Building on this observation, they are investigating the molecular relationship between mitochondrial dysfunction and telomere dysfunction with a focus on telomerase itself. Specifically, they are investigating the biological significance of telomerase regulation by reactive oxygen species and the importance of this relationship in the development of metabolic syndrome and cardiovascular disease in collaboration with the lab of Marschall Runge.
Pharmacological Control of Social Behavior
Neuronal development and processing are complex and poorly understood. One major question that has significant consequences for society is the biological basis for subtle and complex social interactions for example mother-child bonding, interpersonal trust, social awareness, and social approach. Using animal models for social behaviors, Jarstfer’s lab is exploring the pharmacological basis for social behavior by conducting preclinical testing of small molecules that offset social deficits.