eIF2B in Control of the Integrated Stress Response

Speaker

Carmela Sidrauski
Principal Investigator
Calico Life Sciences

Abstract

We study stress signaling pathways and the numerous factors that maintain proteins in a functional state in the human cell, often referred to as the proteostasis network. We aim to understand the function and dynamics of these networks in neurodegeneration and normal aging. We use a variety of techniques, ranging from biochemistry, cell biology, genetics, and genome-scale molecular approaches, to unravel the changes that take place in disease and during aging.

We have focused our efforts in the last few years on the integrated stress response (ISR). This is a conserved signaling pathway that attenuates the rate of protein synthesis and reprograms the cell upon a wide variety of insults. This central regulatory node modulates bulk protein synthesis as well as induces preferential expression of stress proteins in a highly dynamic fashion to restore homeostasis. We are interested in exploring the physiological inputs that induce this response as well as the cell autonomous and non-cell autonomous outputs of the pathway in mammals. The ISR is induced in various disease contexts but its contribution to pathogenesis is not well understood. We utilize both genetic and pharmacological tools to interrogate the impact of ISR activation in cellular and organismal physiology in health and in disease states.

Biography

Dr. Sidrauski is a Principal Investigator in Calico Life Sciences in South San Francisco. She has ample experience in both academia and in industry in deciphering molecular mechanisms of stress responses in mammalian cells. During her work as HHMI Research Specialist in the laboratory of Peter Walter (UCSF), she discovered ISRIB, a potent small molecule that inhibits the integrated stress response of cells. Currently, she is the biology lead of the discovery team at Calico for investigating the potential of targeting of the integrated stress response for therapeutic purposes. 

Dr. Sidrauski earned her M.S. degree in biology from the Universidad de Buenos aires in Argentina, and then she earned her PhD degree from UCSF in 1998. Her graduate and post-doctoral work led to fundamental discoveries on the molecular mechanism of the unfolded protein response.