BCIRM Interns pushing frontiers of knowledge

Click link for full color version  2019-2020 Cohort

Amber Morey

Pursuing M.S. in Cell and Molecular Biology at SDSU Amber is doing her internship at Sanford Consortium for Regenerative Medicine (SCRM), under the direction of Dr. Louise Laurent. The focus of her project is to examine exRNAs that are isolated from extracellular vesicles released by a range of placental tissues – including BeWo (placental cancer cell line), placental explants, and stem cell-derived trophoblasts. She will be continuing in this lab for another year and will use this project for her master’s thesis. Her SDSU home mentor is Ralph Feuer.

Jasmine Chavez

Jasmine chose to intern at the Salk Institute for Biological Sciences in the lab of Juan Carlos Izpisua Belmonte. This lab utilizes a variety of cell types with the overarching goal of studying gene expression, regeneration, and aging. Her main research was done under the supervision of Tomoaki Hishida with a focus on liver regeneration in vivo through transient expression of the Yamanaka 4 factors. She also worked on projects involving neural stem cells and astrocytes, with Reyna Benitez-Hernandez, studying the effects of different metabolites on cell state. She is currently pursuing her  Masters in Cell and Molecular Biology at SDSU in the Grainger lab.

Sharon Sengphanith

Sharon is a fifth year undergraduate student working in Dr. Matthew Shtrahman’s lab at the Sanford Consortium for Regenerative Medicine. Her lab previously found that recombinant adeno-associated virus (rAAV) kills dividing neural stem cells in the hippocampus and has led them to believe that rAAV has potential oncolytic activity against Glioblastoma cancer stem cells. Because it is believed to be a relatively safe and efficient viral vector with no known significant toxicity or pathogenicity, rAAV is a promising therapeutic for this disease. For  her project, Sharon uses both in vitro and in vivo methods in order to study the mechanisms behind the viral effects of rAAV on Glioblastoma. The overall goal of this project is to identify and optimize parts of the virus in order to kill these cancer stem cells to use as a potential clinical therapeutic.

Willi Cheung studies the effect of LMX1A in the generation and differentiation of dopaminergic neurons from iPSCs. The degeneration of dopaminergic neurons of the midbrain is one of the major hallmarks of Parkinson’s disease (PD), the second most common neurodegenerative disease. iPSC-derived dopaminergic neurons have been generated to model PD. Prior studies have shown that a combination of the transcription factors ASCL1, NURR1 (alone or together with LMX1A) directly reprogrammed mouse fibroblasts to functional induced dopaminergic neurons. Previous studies permitted to detect the expression of key dopaminergic neurons defining genes tyrosine hydroxylase (Th) and dopamine decarboxylase (Ddc) in induced neuronal cells generated with ASCL1 and NURR1. However, dopamine transporter DAT could not be detected in any induced neuronal cell population. Thus, the study of transduction of ASCL1 and NURR1 alone or in combination with LMX1A is fundamental to understand whether LMX1A is essential for neuronal maturation in the dopaminergic system.

Samantha Trescott

Samantha studies the pathophysiology of Neurodegenerative Langerhans Cell Histiocytosis (LCH), a rare disorder characterized by an accumulation of abnormal histiocytes. LCH results in a broad range of clinical symptoms from single bone lesions to multisystem disease associated with high morbidity and mortality. LCH is most often caused by a somatic B-Raf (BRAF) mutation in the MAPK/ERK pathway with the most common point mutation being V600E.  The working hypothesis of this project is that LCH associated neurodegeneration, caused by the somatic BRAF mutation in EMPs leads to a subpopulation of microglia carrying the BRAF mutation, then microglia become abnormally activated. Therefore, an in vitro model can be generated using patient-derived human-induced pluripotent stem cells (hiPSCs) to show that the pathophysiology of neurodegeneration associated with LCH is in part due to microglial overactivation or dysregulation in the MAPK/ERK pathway. The model developed in this study will help to elucidate how the improper functionality of microglia can be applied to other neurodegenerative diseases such as Parkinson’s and Alzheimer’s Disease.

Emily Morgan studies cardiomyopathy by mimicking fibrosis and inducing stress into iPSC-derived cardiomyocytes.  Muscle cells known as Cardiomyocytes are the contractile cells that make up the heart. Typically, aging and genetic mutations can contribute to heart dysfunction such as dilated Cardiomyopathy (DCM) where the heart enlarges and ventricle walls weaken. While many homozygous mutations can lead to DCM, it is less clear with heterozygous mutations. However in a family with a history of DCM, an enhanced rates of early onset DCM was observed, and was linked to the presence of two heterozygous mutations in the genes VCL and TPM1 (Deacon, 2019). Using induced pluripotent stem cells (iPSCs), Emily is trying to better understand how this specific combination of mutations contributed to disease, by generating patient-specific cardiomyocytes (CMs). While baseline performance of the iPSC-CMs was reduced, Emily and colleagues are trying to determine to what extend additional stress could induce disease in unaffected carriers of VCL and TPM1 mutations. They anticipate that this data will highlight the need to study gene-environment connections more closely.

Carolina Cano’s study focuses on senescence-associated inflammation in Alzheimer’s disease.  Research on the biology of aging show increased disease vulnerability with age. Senescent cells (SC) are abnormal cells that accumulate with age. SCs express a senescence-associated secretory phenotype (SASP), which is characterized by an arrest of cell proliferation and the secretion of inflammatory factors. Carolina and colleagues have shown that inflammation associated with SASP depends on a mitochondria-to-nucleus retrograde signaling pathway. They show progress on models of microglial senescence, including the development of assays for markers of senescence and inflammation using human induced pluripotent stem cell (iPSC) approaches in vitro and animal models in vivo. The approach using these cell lines as a novel model to screen for drugs that block SASP-associated inflammation in microglia, including drugs which are already clinically available. This work can identify novel therapeutic targets for treatment of AD and novel mechanisms of senescence that underlie age-associated disease.

Denay Stevens studies the effect of drugs that induce E2A activity on pancreatic ductile adeno carcinoma (PDA) stemness.  PDA has a 5-year survival rate of only 9 percent, presenting the desperate need to better understand the molecular mechanisms involved in pancreatic cancer progression.  Mutations in Kras, P53, P16, and SMAD are major drivers of PDA progression. Additionally, PDA is characterized by high levels of the stem cell driver MYC and dysregulation of the retinoblastoma (RB) tumor suppressor. Together, these aberrations promote tumorigenesis through uncontrolled proliferation and dedifferentiation. Previous research in our lab discovered that the bHLH transcription factor E2A gene is repressed in PDA progression and that restoration of E2A activity induced growth arrest through downregulation of MYC and upregulation of P21, which subsequently promoted RB activity. Simultaneously, this corresponded to a loss of stem cell-like characteristics and induced cellular differentiation. Thus, a screening platform to identify drugs that induce E2A activity was developed. Denay project is to investigate the effectiveness of the two FDA approved drugs,  Pitavastatin and Vorinostat individually and in combination, to control tumorigenesis and the cancer stem cell population in PDA. Preliminary results of in vitro studies show that the drugs function in synergy to downregulate MYC expression and induce P21 expression, which restores RB activity, significantly depleting cell growth. Mouse xenograft studies are underway. It is expected that that drugs promoting E2A activity in PDA will demonstrate an advantage in reducing the stem cell phenotype in PDA.