Specific Examples of Resident Research
Autophagy in Development and Disease
Autophagy is an intercellular pathway that is essential to the development and function of all major organs. Disorders of this pathway offer a unique opportunity to understand the importance in health and disease – a concept that recent residents Lara Wahlster and her husband, Darius Ebrahimi-Fakhari, explore on a clinical, genetic and molecular level. While Lara’s work has focused on congenital anemias and hematopoiesis, Darius is interested in neurogenetic diseases and movement disorders. Their scientific paths often cross around autophagy.
Working with George Daley at Children’s Lara generated hematopoietic progenitor cells from induced pleuripotent stem cells of patients with Diamond-Blackfan anemia (DBA). Using an unbiased chemical screening she helped identify SMER28, a small molecule inducer of autophagy that enhances erythropoiesis in a range of in vitro and in vivo models of DBA (Nat Cell Biol). These findings point to autophagy as a therapeutic pathway in DBA (Sci Transl Med). As a resident in the accelerated research pathway, Lara worked with her mentor and former BCRP graduate Vijay Sankaran to identify genetic variants that affect engraftment and clinical outcomes after stem cell transplantation.
As a student in the lab of Pamela McLean at MGH, Darius became interested in the role of autophagy in neurons, when he found that the Parkinson’s disease associated protein α- synuclein is targeted by this pathway (J Neurosci, Autophagy). In Mustafa Sahin’s laboratory at Children’s, he used Tuberous Sclerosis Complex (TSC) as a genetically tractable model of mTORC1-dependent autophagy in neurons (Cell Rep). For this work, Darius was awarded the Outstanding Junior Member Award from the Child Neurology Society and the Outstanding Investigator Award from the German Society for Pediatric Neurology. In addition, Darius has led several clinical research projects aimed at understanding rare genetic movement disorders associated with PRRT2 mutations (Neurology, Brain) and more recently hereditary spastic paraplegia type SPG47, a disorder again linked to deficits in autophagy. Most of his work is inspired by patients and families that he cared for as a medical student and as a BCRP resident.
In other studies, Lara and Darius collaborate on diseases that share both hematologic and neurological problems, such as the lysosomal storage disorders (Hum Mol Gen). Following their research and clinical interests, Lara began a Hematology/Oncology Fellowship this year and Darius joined the Child Neurology Residency after graduating from the BCRP.
Health Outcomes
As an MD/PhD student at Yale, recent resident Emily Bucholz studied socio-demographic disparities in health outcomes and quantified the long-term impact of quality metrics on patient life expectancy. She continued her work in quality measurement as a pediatric resident in the Integrated Research Pathway (IRP) studying pediatric readmissions under the mentorship of Dr. Mark Schuster and Dr. Jay Berry. Her work focused on characterizing the timing and causes of pediatric readmissions as well as the association of pediatric and adult readmissions and trends over time. The goal of this research was to better understand when children are at greatest risk of readmission, how patterns of readmission vary by index diagnoses and causes of readmission, and whether large-scale readmission efforts in adult populations have had an effect on pediatric readmissions. In addition, she continued to investigate socio-demographic disparities in health outcomes among children with single ventricle heart disease and disparities in cardiovascular risk factor awareness among young adults. She has been awarded young investigator awards by both the American Heart Association and the American College of Cardiology; and more recently, her work evaluating the relationship between hospital performance and patient life expectancy (N Engl J Med) was awarded one of the Top 10 Clinical Research Achievement Awards of 2017 by the Clinical Research Forum.
Emily is currently a pediatric cardiology fellow at Boston Children’s Hospital.
