Dr. Deepak Srivastava is the Younger Family Director and a Senior Investigator at the Gladstone Institute of Cardiovascular Disease and Director of the Roddenberry Center for Stem Cell Biology at Gladstone. At the University of California, San Francisco (UCSF), Dr. Srivastava is also a Professor in the Departments of Pediatrics, and Biochemistry & Biophysics, and is the Wilma and Adeline Pirag Distinguished Professor in Pediatric Developmental Cardiology. Dr. Srivastava completed his undergraduate degree at Rice University, medical training at the University of Texas Medical Branch in Galveston and his residency in the Department of Pediatrics at UCSF. He also did a fellowship in pediatric cardiology at the Children’s Hospital of Harvard Medical School and a postdoctoral fellowship at the M.D. Anderson Cancer Center, before joining the faculty at UTSW in 1996.
Before joining Gladstone in 2005, Dr. Srivastava was a Professor in the Department of Pediatrics and Molecular Biology at the University of Texas Southwestern (UTSW) Medical Center in Dallas. He has received numerous honors and awards, including endowed chairs at both UTSW and UCSF, as well as election to the American Society for Clinical Investigation, the American Academy of Arts and Sciences, the American Association for the Advancement of Science and the National Academy of Medicine. Dr. Srivastava’s laboratory has trained more than 50 postdoctoral fellows and graduate students.
Title of Abstract
Engineering of gene networks that stabilize cell fate and behavior would allow full control over biological process and disease-related changes in cell states. To accomplish this, it is necessary to deeply understand the establishment of normal networks and how they are perturbed in disease. We have focused our efforts on heart disease, a leading cause of death in adults and children. We have described complex signaling, transcriptional and translational networks that guide early differentiation of cardiac progenitors and later morphogenetic events during cardiogenesis. By leveraging these networks, we have reprogrammed disease-specific human cells in order to model genetically defined human heart disease in patients carrying mutations in cardiac developmental genes. These studies revealed mechanisms of haploinsufficiency and we now demonstrate the contribution of genetic variants inherited in an oligogenic fashion in congenital heart disease. We also utilized a combination of major cardiac developmental regulatory factors to induce direct reprogramming of resident cardiac fibroblasts into cardiomyocyte-like cells with global gene expression and electrical activity similar to cardiomyocytes, and have revealed the epigenetic mechanisms underlying the cell fate switch. Most recently, we identified an approach to unlock the cell cycle in adult cardiomyocytes by introducing fetal cyclins and cyclin dependent kinases, and have been able to induce resident, post-mitotic cardiomyocytes to undergo cell division efficiently enough to regenerate damaged myocardium. Knowledge regarding the early steps of cardiac differentiation in vivo has led to effective strategies to generate necessary cardiac cell types for disease-modeling and regenerative approaches, and may lead to new strategies for human heart disease.
Dr. Srivastava’s laboratory revealed how cardiac chamber-specific gene networks are established at the transcriptional level and are integrated with signaling pathways. His laboratory used human genetics to demonstrate that a decrease in dosage of some of these cardiac developmental regulators can cause human cardiac septal defects and valve disease, and is now using induced pluripotent stem cells to discover the mechanisms of disease in these patients. In studying the regulation of gene dosage, his lab described the first known biological role of a microRNA in the mammalian system, ultimately revealing a network of microRNAs that titrate the dose of key cardiac gene networks that dictate cell fate and differentiation. Dr. Srivastava’s lab has leveraged the body of knowledge from cardiac developmental biology to reprogram non-muscle cells in the mouse heart directly into cells that function like heart muscle cells, effectively regenerating heart muscle after damage. This new paradigm of harnessing endogenous cells to regenerate organs may be broadly applicable to other organs. Such approaches to understand human disease promise to yield new therapies. Dr. Srivastava has co-founded a biotechnology company to help find new cures for many human diseases and one of the developmental genes whose role he discovered, Thymosin β4, is currently in clinical trials for patients suffering ischemic damage to the heart.