2020-21 Stem Cell Biological Engineering Fellows
Jesse Dunnack
Pedigree studies in familial Parkinson’s Disease have identified mutations in over 20 genes that are directly implicated in its pathophysiology. However, the molecular mechanisms that underlie sporadic Parkinson’s Disease (~90% of cases) are less well characterized. Recent GWAS studies have pinpointed common variants that link ~300 genes to the etiology of sporadic Parkinson’s Disease. In efforts to parse out the functional interactions between these variants and explore how they contribute to one’s risk of developing Parkinson’s Disease, my project will take a functional genomics approach. Starting with human embryonic stem cells expressing CRISPRi or CRISPRa machinery, my research will utilize monolayer and 3D organoid cell culture systems to address these questions by means of Perturb-Seq screens. Our group hopes that the resulting transcriptional profiles and splicing pattens will inform upon the functional interactions that underlie an individual’s risk of developing Parkinson’s Disease.
Quincy Huynh
Translating stem cell therapies to humans requires a non-invasive longitudinal imaging method that can track the distribution of the transplanted stem cells. Magnetic Particle Imaging (MPI) is a radiation-free, positive contrast imaging modality with great promise for stem cell tracking that has been shown to track stem cells for over 80 days with 200 cell per voxel sensitivity. My project is to design and implement an optimized front end hardware and electronics that will enable even higher resolution, higher sensitivity, and quantitative, robust imaging of stem cells in vivo using MPI.
Hannah Karp
Developing gene therapy vectors that restrict delivery to specific target cell types is critical to enable in vivo therapies. Ex vivo gene therapy trials have shown the promise of lentiviral vectors in treatment of genetic disorders. However, most lentiviral-type vectors used in ex vivo therapies have broad tropisms, making them non-ideal for in vivo applications. Utilizing a novel tyrosinase-mediated bioconjugation method, I aim to develop a modular lentiviral vector re-targeting strategy. Once developed, I intend to optimize vector transduction and gene editor delivery in clinically relevant cell-types, particularly hematopoietic stem cells.
Sean Kitayama
Metastasis is responsible for ~90% of cancer-related deaths. It relies on an intricate interplay between multiple microenvironments at the primary tumor and distant sites. This dissemination is driven by an epithelial to mesenchymal transition (EMT), leading to a subset of cells adopting a cancer stem cell phenotype, and promoting tumor propagation and invasion. Shortcomings of traditional in vivo metastasis models include imaging challenges, limited reproducibility and a lack of physiological relevance. In contrast, we are utilizing a high-throughput, single-cell DNA-directed patterning method to recapitulate secondary microenvironments in vitro to investigate how extracellular vesicles prepare the pre-metastatic niche for EMT-driven metastasis.
Colin Skinner
A prominent model of aging posits that organisms age because of the decline in stem cell proliferative and regenerative potential. Previous studies with murine heterochronic parabiosis demonstrated that the arrow of aging is not unidirectional, however, and that the regenerative decline of stem cells can be reversed. Systemic delivery of oxytocin or Alk5 inhibitor in aged mice restores the rejuvenating capacity of muscle stem cells and hippocampal neurogenesis, respectively. These findings suggest a potential cause of aging at the transcriptional level, consistent with evidence that epigenetic modifications are closely linked with the aging process. My research focuses on identifying potential epigenetic signatures of aging in stem cells using computational epigenetics and machine learning methods. Such signatures, if present, can provide a systems-level understanding of the epigenomic and transcriptomic changes with aging, and help inform possible pharmacological therapies for aging.
Kevin Wickham
Reversible exit from the cell cycle, known as cellular quiescence, is a feature of many cells in the body, including stem cells. The ability of a subset of stem cells to exit and re-enter the cell cycle is key to development and tissue repair throughout life. Evidence suggests that the unfolded protein response of the ER (UPRER), an ancient and highly conserved cellular response to the accumulation of unfolded proteins and/or disruptions in the lipid bilayer of the ER, is key to governing functional quiescence and cell-cycle re-entry. When activated the UPRER results in transcriptional changes that help restore ER function. As an organism ages, the capacity of stem cells to re-activate from quiescence declines, as does their ability to repair damaged tissues. I propose to determine the role of ER homeostasis in a C. elegans model of quiescence and translate these finding to neural stem cells that can be used as a tractable and physiologically relevant in vitro system to study quiescence and re-activation in human cells.