Leveraging rare disease genetics to illuminate specialized cell biology
About the laboratory
The Chivukula Lab is housed within the Center for Genomic Medicine at Massachusetts General Hospital and Harvard Medical School. We are located in the state-of-the-art Simches Research Building on the MGH main campus.
We use a combination of molecular biology, biochemistry, and animal modeling approaches to investigate mechanisms underlying human genetic disorders. We are particularly interested in rare Mendelian diseases that dysregulate the biogenesis and function of specialized subcellular compartments. We are the grateful beneficiaries of funding support from Mass General Hospital, the Francis Family Foundation, the Burroughs Wellcome Fund, and the Ellison Foundation.
Lab members & alumni
Raghu Chivukula
Group Leader
Raghu Chivukula, MD, PhD is Assistant Professor of Medicine and Surgery at Harvard Medical School, Group Leader in the Center for Genomic Medicine at Massachusetts General Hospital, and Associate Member of the Broad Institute of MIT and Harvard. In addition to directing a research program, he attends to patients at Mass General in the intensive care unit and co-directs the Mass General adult pulmonary genetics program.
Raghu studied cellular and molecular neuroscience at Johns Hopkins University prior to medical and graduate training in human genetics and molecular biology at Johns Hopkins University School of Medicine. He completed a residency in internal medicine at Massachusetts General Hospital, clinical fellowships in pulmonary disease and critical care medicine at Harvard Medical School, and postdoctoral research training at the Whitehead Institute for Biomedical Research. His work has been recognized by the Michael A. Shanoff Award, Forbes Magazine “30 Under 30”, the Parker B. Francis Fellowship, the Burroughs Wellcome Career Award for Medical Scientists, the Donahoe Catalyst Award, and the American Society for Clinical Investigation Young Physician-Scientist Award. Link to CV.
When he is not busy with lab or hospital work, Raghu enjoys climbing and trying to get his 1975 Porsche 911 to start.
Jack Bush
Research Technician
Jack has a background in marine biology and is working with mouse genetic models of lung disease.
David Ziehr
HMS Instructor in Medicine
After medical school at Harvard, David completed clinical training in pulmonary and critical care medicine at MGH. David is interested in the molecular pathophysiology of pulmonary fibrosis.
Max Valenstein
HMS medical student
After undergraduate training at Yale, Max matriculated to the Harvard/MIT MD/PhD program and defended his thesis in 2022. Max is planning a career in academic medicine as a physician-scientist.
Lillie Chudacoff
Summer student alumna
Lillie worked in the lab during the summer of 2023 as a visiting undergraduate student from Eckerd College. Lillie is now pursuing PhD training in Chemistry.
Yunhan (Forrest) Xu
Research Technician
Forrest is a technician in the lab working on the biochemical consequences of GGC trinucleotide repeat expansions.
Jason Yang
Research Technician alumnus
Jason and Raghu first worked together when Jason was an MIT undergraduate and Raghu a postdoctoral fellow, following which Jason was the first member of the Chivukula lab. Jason is now a genetics PhD student at Stanford.
Research areas
Our lab is grounded in the belief that rare human genetic disorders can (1) illuminate fundamental principles in cell biology and (2) reveal new treatments for common and uncommon disease alike. These ideas have already paid huge dividends in heart disease and cancer and are growing in scope as medical practice increasingly incorporates molecular genetics.
We are currently most interested in monogenic disorders of proteostasis and organelle quality control. It is now clear that proteostasis and organellar defects, often manifested by subcellular protein aggregation, are common during aging as well as diverse human disease states. Uncovering the molecular basis of such disorders is difficult owing to limitations in model systems and a poor understanding of the initiating events in complex, often age-related diseases. We are therefore taking a genetics-driven approach to meet this challenge. Our strategy focuses on leveraging human genetic syndromes that phenocopy sporadic proteostasis and organellar diseases but have a single defined cause amenable to mechanistic investigation in the laboratory. We employ model systems including cultured immortalized cells, primary human stem cell cultures, and mouse models of disease and apply molecular biology, biochemistry, mass spectrometry, advanced microscopy, and functional genomics approaches to tackle these questions!
1 / Familial bronchiectasis
Bronchiectasis describes a family of related pulmonary disorders caused by failure of airway mucociliary clearance. In most cases, the underlying cause of bronchiectasis remains unknown and there are few effective therapies for affected patients. We are therefore leveraging familial forms of the disease to identify novel genetic mechanisms that initiate and exacerbate bronchiectasis. In recent work, we revealed that dysfunction of a previously orphan protein kinase causes bronchiectasis through defects in the growth and/or assembly of airway cilia -- specialized organelles critical for mucociliary clearance. We are actively working to understand the molecular basis of this and other forms of Mendelian airway disease by applying molecular genetics and biochemistry methods to in vitro airway culture systems.
2 / Hereditary pulmonary fibrosis
Pulmonary fibrosis (scarring) is an incurable disorder caused by a large, heterogenous, and poorly understood family of "interstitial lung diseases". Notably, rare familial forms of pulmonary fibrosis are caused by genetic mutations in factors required for the biogenesis and trafficking of specialized subcellular organelles unique to the lung and are accompanied by accumulation of aggregated proteins and lipids within these compartments. We have recently developed new methods for purifying and analyzing these organelles from genetically engineered mice and are actively working to understand their biochemical roles in lung disease.
3 / Mendelian neurodegeneration
Pathogenic expansions of GGC trinucleotide repeats cause a family of related neurodegenerative disorders typified by intranuclear aggregates. The precise composition and cellular consequences of these aggregated proteins remains unclear and is unknown why GGC repeat diseases specifically affect the brain. We recently developed methods to address these questions and revealed an unexpected link between protein aggregation, tRNA processing, and brain disease. We are actively working to understand the molecular details of this process and, more generally, are interested in understanding the role of tRNA dysregulation in human disease states.
Contact & join us!
Address
185 Cambridge Street
CPZN 6.256
Boston, MA 02114
Applicants
We are always on the lookout for curious, talented, and motivated individuals to join our group. If you are interested in Mendelian genetics, cell biology, and human disease, we would love to connect! Interested research technicians, students, post-doctoral fellows, clinical fellows, and staff scientists should email Raghu to discuss potential opportunities and projects.
Giving
We are deeply grateful for all philanthropic support for our work - no gift is too small. Please direct any gifts supporting the Chivukula Lab here.
