Rapid iPSC "Inclusionopathy" Models to Accelerate Diagnostic and Therapeutic Discovery in Synucleinopathies
Event details
| Date | 23.03.2023 |
| Hour | 10:00 › 11:00 |
| Speaker | Prof. Vikram Khurana, M.D., Ph.D., Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (USA) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
BIOENGINEERING SEMINAR
Abstract:
In neurodegenerative proteinopathies, intracellular inclusions are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. Patient- derived iPSC models, while promising for disease modeling, do not form analogous inclusions in a reasonable timeframe and suffer from limited tractability and scalability. In this talk, I will describe an iPSC toolbox that utilizes piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of misfolding-prone proteins. The system is scalable and amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron alpha-synuclein inclusionopathy models have been engineered to form inclusions spontaneously or through exogenous seeding by alpha-synuclein fibrils. These models recapitulated known fibril- and lipid-rich inclusion subtypes in human brain, shedding light on their formation and consequences. Genetic-modifier and protein-interaction screens identified sequestered proteins in these inclusions, including RhoA, that were deleterious to cells when lost. Finally, I will discuss how this new iPSC platform could facilitate biological, diagnostic and therapeutic drug discovery for neurodegenerative proteinopathies.
Bio:
Dr. Khurana is Chief of the Division of Movement Disorders at Brigham and Women’s Hospital and Harvard Medical School. He is Principal Faculty at the Harvard Stem Cell Institute, and an Associate Member of the Broad Institute of Harvard and MIT. He is a member of the Board of Directors of the MSA Coalition. His clinical and research interests relate to neurodegenerative disorders focusing on Parkinson’s disease (PD) and related dementias, rarer disorders including multiple system atrophy and ataxias.
Dr. Khurana is a medical graduate of the University of Sydney, Australia, and came to Boston as a Fulbright Scholar in 2001, obtaining his Ph.D. in neurobiology from Harvard University in 2006. He completed his neurology residency at Brigham and Women’s and Massachusetts General Hospitals, and fellowship in movement disorders and ataxia at Massachusetts General Hospital, where he was on the faculty from 2012 to 2016. Dr. Khurana received postdoctoral training in the laboratories of Drs. Susan Lindquist and Rudolf Jaenisch at the Whitehead Institute for Biomedical Research (MIT), at which time he led some of the first studies to identify and reverse pathologies in human stem cells derived from PD patients.
His current research continues to bring stem-cell technologies toward personalized and precise diagnostics and therapeutics for neurodegenerative disorders. Dr. Khurana’s research has been recognized through grants and awards, including federal grants from the NIH and Department of Defense, foundation grants from the American Academy of Neurology, Michael J Fox Foundation, Multiple System Atrophy Coalition, National Ataxia Foundation, Parkinson’s Disease Foundation among others. In 2018, he was named a Robertson Investigator of the New York Stem Cell Foundation, in 2019 a George C. Cotzias Fellow of the American Parkinson’s Disease Association and in 2020 an investigator of the Aligning Science Across Parkinson’s Initiative.
Zoom link for attending remotely: https://epfl.zoom.us/j/61378478243
Abstract:
In neurodegenerative proteinopathies, intracellular inclusions are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. Patient- derived iPSC models, while promising for disease modeling, do not form analogous inclusions in a reasonable timeframe and suffer from limited tractability and scalability. In this talk, I will describe an iPSC toolbox that utilizes piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of misfolding-prone proteins. The system is scalable and amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron alpha-synuclein inclusionopathy models have been engineered to form inclusions spontaneously or through exogenous seeding by alpha-synuclein fibrils. These models recapitulated known fibril- and lipid-rich inclusion subtypes in human brain, shedding light on their formation and consequences. Genetic-modifier and protein-interaction screens identified sequestered proteins in these inclusions, including RhoA, that were deleterious to cells when lost. Finally, I will discuss how this new iPSC platform could facilitate biological, diagnostic and therapeutic drug discovery for neurodegenerative proteinopathies.
Bio:
Dr. Khurana is Chief of the Division of Movement Disorders at Brigham and Women’s Hospital and Harvard Medical School. He is Principal Faculty at the Harvard Stem Cell Institute, and an Associate Member of the Broad Institute of Harvard and MIT. He is a member of the Board of Directors of the MSA Coalition. His clinical and research interests relate to neurodegenerative disorders focusing on Parkinson’s disease (PD) and related dementias, rarer disorders including multiple system atrophy and ataxias.
Dr. Khurana is a medical graduate of the University of Sydney, Australia, and came to Boston as a Fulbright Scholar in 2001, obtaining his Ph.D. in neurobiology from Harvard University in 2006. He completed his neurology residency at Brigham and Women’s and Massachusetts General Hospitals, and fellowship in movement disorders and ataxia at Massachusetts General Hospital, where he was on the faculty from 2012 to 2016. Dr. Khurana received postdoctoral training in the laboratories of Drs. Susan Lindquist and Rudolf Jaenisch at the Whitehead Institute for Biomedical Research (MIT), at which time he led some of the first studies to identify and reverse pathologies in human stem cells derived from PD patients.
His current research continues to bring stem-cell technologies toward personalized and precise diagnostics and therapeutics for neurodegenerative disorders. Dr. Khurana’s research has been recognized through grants and awards, including federal grants from the NIH and Department of Defense, foundation grants from the American Academy of Neurology, Michael J Fox Foundation, Multiple System Atrophy Coalition, National Ataxia Foundation, Parkinson’s Disease Foundation among others. In 2018, he was named a Robertson Investigator of the New York Stem Cell Foundation, in 2019 a George C. Cotzias Fellow of the American Parkinson’s Disease Association and in 2020 an investigator of the Aligning Science Across Parkinson’s Initiative.
Zoom link for attending remotely: https://epfl.zoom.us/j/61378478243
Practical information
- Informed public
- Free
Organizer
- Prof. Hilal Lashuel, EPFL