The long-term goal of our research program is to better understand the age- and disease-linked deficits in protein homeostasis that contribute to disease-related cardiac dysfunction, and to use this understanding to identify cellular targets that may serve as viable new therapeutic candidates.

A major research direction of our lab is to study how heart disease affects gene expression at the post-transcriptional level, which is of major importance for maintaining protein homeostasis. We also study adaptive responses of the heart mediated by proteins secreted by the heart, in order to define potential therapeutic approaches that use the heart’s natural defenses.

The Doroudgar Lab is part of the Translational Cardiovascular Research Center (TCRC) in the Department of Internal Medicine at the The University of Arizona College of Medicine – Phoenix.

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News

September 2023

Check out our editorial on the publication by Yang et al. from XJ Wang’s lab, which provides the first genetic examination of a proteasome phosphosite in animals, showing cAMP-dependent PKA (protein kinase A)-induced proteasome activation protects against proteotoxicity.

Dr. Aghajani presented her work at the Arizona Postdoctoral Research Conference on 9/22/23 at the UA College of Medicine-Phoenix, Phoenix Bioscience Core, Virginia G. Piper Auditorium.

August 2023

Christoph Hofmann’s exciting new paper “mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes" is published in the American Journal of Physiology-Heart and Circulatory Physiology! Here, we found that mTORC1 is transiently activated early in response to ER stress and is essential for the upregulation of adaptive unfolded protein response genes and cell survival. Great job, Christoph and team!

Shirin delivers Department of Internal Medicine Grand Rounds on Friday 8/25/23.

June 2023

Ngunyi Ellis Fuangunyi, undergraduate majoring in Physiology at the University of Arizona – Tucson, starts his summer internship in the lab. Welcome Ngunyi! Looking forward to all you will do this summer.

May 2023

Congratulations to Dr. Marjan Aghajani! Dr. Aghajani was awarded the prestigious Postdoctoral Research Development Grant. She has received the title of University of Arizona Sursum Fellow. Sursum is Latin for “upwards” and is featured at the center of the University of Arizona seal.

April 2023

Shirin is invited as an Early Career Development Awardee to speak at the University of Arizona College of Medicine Tucson Translational Medicine Workshop on April 15th. What an exciting event and great fun also participating in the panel discussion on career development. Energizing to meet the next generation of investigators beginning their journey!

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Research

Protein Synthesis

Although changes in gene expression represent a fundamental feature of cardiac disease, transcript levels often poorly correlate with respective protein levels, suggesting post-transcriptional gene expression control may be disease-regulated in the heart. We developed a new experimental method to identify which transcripts are actively translated in cardiac myocytes in the diseased mouse heart, in vivo. We combined ribosome profiling with a ribosome-tagging approach that enabled us to isolate and sequence transcripts that are engaged in protein synthesis specifically from mouse cardiac myocytes in vivo; defined as the cardiac myocyte translatome. Using this cell-type–specific Ribo-seq approach, we defined the translational response of cardiac myocytes during hypertrophic stress (pressure overload). This work demonstrates the magnitude of the cellular stress response at the translational level and lays the foundation for discovery of novel molecular mechanisms across all areas of cardiovascular pathophysiology.

Protein Secretion

Our studies of protein secretion began when we turned our attention to the effects of cellular stress and protein misfolding on cellular secretion of critical paracrine proteins, and discovered a unique mechanism of secretion of MANF, a novel ER stress response protein. This study led the way to our research into a more global view of proteins secreted from cardiac myocytes, wherein we examined the cardiac myocyte secretome in response to protein folding stresses.

The ER Stress Response

We previously discovered a novel molecular pathway known as the endoplasmic reticulum (ER) stress response, to be activated when cells or tissues are subjected to ischemia, the loss of oxygen and nutrients. Furthermore, we found that the activation of the ER stress response is necessary to protect cells from death during and after ischemia. In the first study to examine any ER-localized E3 ubiquitin-protein ligase in the heart, we found that cardiac pathology activates the previously unappreciated process of ER-associated protein degradation (ERAD), which moderates pathological cardiac myocyte remodeling. One of the highest impact findings of our work so far is that protein quality control in the ER of cardiac myocytes is a critical component of heart function.

Shirin Doroudgar

Assistant Professor

Department of Internal Medicine

Translational Cardiovascular Research Center (TCRC)

The University of Arizona College of Medicine – Phoenix

Principal Investigator

Shirin Doroudgar, PhD is Assistant Professor of Internal Medicine at The University of Arizona College of Medicine – Phoenix and the Translational Cardiovascular Research Center (TCRC). Her research program utilizes integrative approaches from molecular and organellar to cellular and organismal levels to examine the dynamics of the protein homeostasis network in health and disease. The Doroudgar Lab’s current focus is on studies of cellular stress responses that underlie the dynamic remodeling of the cardiac myocyte proteome and secretome.

Our studies utilize integrative approaches from molecular and organellar to cellular and organismal levels to examine the dynamics of the protein homeostasis network in health and disease. Since protein homeostasis is a critical determinant of cell and organism health, our research focuses on identifying key molecular regulators of protein homeostasis. Our long-term goal is to better understand the age- and disease-linked changes in protein homeostasis that contribute to heart disease, and to use this understanding to identify proteins that could serve as viable candidates as new therapeutic targets. Currently, our research is primarily related to cardiac pathology, but our work has potential applications in other areas, including cancer biology, neurobiology, and regenerative medicine.

Interests

Endoplasmic Reticulum
Protein Secretion
Protein Synthesis
Proteostasis
Cardiovascular Biology

Education

Doctor of Philosophy, Biology, 2012
Department of Biology, University of California, San Diego, CA
Bachelor of Science, Molecular Biology, 2005
Department of Biology, University of California, San Diego, CA