HSU CIRM Scholars Program
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Current HSU-CIRM Scholars

HSU-CIRM Scholars participate in a 12-month, research-intensive internship at the Stanford University Center for Human Embryonic Stem Cell Research and Education, the University of California, San Francisco (UCSF) Institute for Regenerative Medicine, or the University of California, Davis (UCSD) Institute for Regenerative Cures. Scholars receive a monthly stipend of $2,500 in addition to a $5,000 scholarship to be put towards their Humboldt State enrollment fees.

To see a list of past HSU-CIRM scholars, click here.

The 2014-2015 HSU-CIRM Scholars List

HSU-CIRM Host Labs

Hannah Collins - "The role of cell polarity protein Lgl1 in oligodendrocytes precursor cells "
Claudia Petritsch, University of California, San Francisco

The Petritsch lab at UCSF investigates many processes of one of the most important organ in the body, the brain. One of your main goals is to understand the development and maturation of myelinating cells called oligodendrocytes (OLG). OLG cells constituting 2-9% of the total cells in the adult brain are the largest proliferating population. These unique cells originate from oligodendrocyte precursor cells (OPC) that express the NG2 chondroitin sulfate proteoglycan. NG2 + OPC’s have been shown to evenly distribute in the adult brain and remain actively dividing while generating myelinating OLG in grey and white matter tracks including the corpus callosum while remaining committed to the OL linage beyond the perinatal stages. OPC use the evolutionarily conserved process of asymmetric cell division (ACD) to self-renew and differentiate. This process is achieved by polarity proteins, which provide the cells with cues and instruct cell fate determinates to localize unequally throughout the cell, along with properly orientating the spindle fibers. This allows cells to create daughter cells with distinct fates after cytokinesis. We have begun to investigate the WD40 domain polarity protein Lgl1 role in these conserved processes. We have found that Lgl1 is expressed in premyelinating and myelinating OLG in the postnatal and adult brain. We have also shown that Lgl1 regulates ACD and differentiation of corpus callosum derived cells in vitro. Will are now beginning to explore in vivo function of Lgl1 in the adult and postnatal brain though the use on and Lgl1 conditional knockout mouse model where Lgl1 is excised from NG2+ cells.

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Todd Gallagher - "Reprogramming Fibroblasts into Myoblasts: Creating a Regenerative Cell Therapy to Treat Muscular Dystrophy "
Michelle Calos, Stanford University

The Calos lab is focused on creating therapies for the treatment of various muscular dystrophies. Muscular dystrophies are a collection of diseases characterized by increasing muscle weakness and wasting as the affected individual gets older. The most progressive and lethal of these myopathies is Duchenne Muscular Dystrophy, DMD is the result of a mutation in the dystrophin gene. This disease is sex linked, affects 1 in 3500 live male births and causes wasting to the muscles of the skeletal and cardiac systems. The dystrophin protein tethers the extra cellular matrix with the cytoskeleton of the muscle fiber. Through normal life processes muscle undergoes constant tearing and repair. The cells responsible for myofiber regeneration are called satellite cells. After muscle damage satellite cells are signaled to proliferate and differentiate into myoblasts, which then fuse with damaged fibers. DMD results in over proliferation and exhaustion of satellite cells. To combat this disease I use a novel immunocompromised dystrophic mouse model, NRG mdx4CV to show the validity of a regenerative cell therapy. Through the controlled overexpression of the muscle master gene MyoD it is possible to reprogram dermal fibroblasts into myoblasts. I do this with fluorescently labeled cells from a wild type mouse and through intramuscular injection I engraft the therapeutic cells into the Tibialis Anterior muscle of the dystrophic mouse allowing the reprogramming to occur in vivo, ameliorating the dystrophic phenotype, while also creating dystrophin producing satellite cells and thus providing a lasting remedy for duchenne muscular dystrophy.

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Sergio Fitch - "Engineering Adipose Stem Cells with Nanoparticles Against Malignant Brain Tumors"
Fan Yang, Stanford University

The Fan Yang Laboratory focuses in Biomaterials and Stem Cells engineering for tissue engineering and targeted drug delivery. One of the major focuses of the lab is the eradication of glioblastoma multiforme (GBM) using adipose derived stem cells (ADSCs). Due to the delicate anatomical location of GBM (the brain), surgical removal is often times precluded, dramatically reducing clinical outcomes. Adipose derived stem cells are an abundant source of adult stem cells that possess unique tumor-tropic abilities coordinated by a myriad of tumor-secreted signals. Exploiting this knowledge, we sought to engineer ADSCs with the anti-apoptotic agent Tumor Related Apoptosis-Inducing Ligand (TRAIL), which selectively induces programmed cell death in tumor cells while leaving normal cells intact. This way, TRAIL overexpressing ADSCs could selectively “seek and destroy” GBM cells. To accomplish this, we circumvented the caveats of viral gene delivery by using an in-house developed polymeric transfection technique to modify ADSCs for TRAIL overexpression. So far, our in vivo studies show improved survival and tumor mass reduction upon application of modified ADSCs to tumor-bearing mice. Our results indicate that ADSCs mediated drug delivery is a feasible therapy with tremendous therapeutic potential against TRAIL sensible cancers. Currently, we are working on a combination therapy using TRAIL-ADSCs and histone deacetylase inhibitors (HDACi) to synergize the apoptotic potential against GBM.

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Jessica Fuhriman - "The Role of p63 in Psoriasis"
Peter Marinkovich Stanford University

Psoriasis is the most common inflammatory skin disease affecting 1-3% of the world’s population. Both keratinocyte cells and immune cells are central in the disease pathogenesis. The Marinkovich Lab at Stanford University has established that psoriatic keratinocytes have an intrinsic predisposition for Rac1 hyperactivation. Rac1 is a small GTPase known to regulate many important cellular processes, including those mediating cell cytoskeletal rearrangements, cellular migration, cell-cell adhesion, and the cell cycle. Through ectopic overexpression of mutant hyperactive V12Rac1 in keratinocytes, we can induce phenotypes closely resembling human psoriasis through stimulation with psoriatic immune cells or inflammatory cytokines both in vivo and in vitro. It is known that psoriatic epidermis has a marked increase of proliferating cells that abnormally extends into suprabasal layers of the epidermis. Furthermore, cells in the suprabasal layers of psoriatic epidermis express proteins that are only normally expressed in basal keratinocytes, indicating that there is an increased number of cells in a more progenitor-like state in psoriatic skin. This is of interest because previous studies have demonstrated that Rac1 is necessary for maintenance of epidermal stem cells. One key protein that regulates keratinocyte differentiation is p63, and we hypothesize that there may be abnormalities of p63 expression or function in psoriatic epidermis with hyperactive Rac1, causing a delay in differentiation of psoriatic keratinocytes. To study p63, V12Rac1 is ectopically expressed in keratinocytes to prime a psoriatic signaling cascade that, upon proinflammatory cytokine stimulation, will enable us to elucidate what may be occurring with p63 expression and function in psoriatic epidermis, and unravel how hyperactive Rac1 may perturb psoriatic keratinocyte differentiation and proliferation.

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Wes Jenkins - "Searching for exRNA Transfer in Early Development"
Michael McManus, University of California San Francisco

Increasing evidence suggests cell-to-cell communication is possible via extracellular RNAs (exRNAs). Regulation of gene expression through microRNAs (miRNAs) has long been established as an endogenous mechanism for fine-tuning expression post-transcriptionally. These small RNAs can prevent translation by binding to the 3’-UTR (untranslated region) of a target mRNA transcript. Recently, many studies have suggested miRNAs can act intercellularly (as exRNAs), potentially broadening their role in many biological processes. A vast number of miRNAs have been identified in the extracellular environment in a variety of bodily fluids, often packaged inside of extracellular vesicles (EVs). Some studies have suggested roles for exRNAs in many important biological processes including stem cell maintenance, apoptosis, and cancer metastasis. However, very little is known about the scope and extent to which exRNAs might mediate communication between cells. This is largely due to the difficulty involved with the identification and functional assessment of exRNAs in-vivo. To address these issues, I seek to employ a novel sensor system to identify functional micro-exRNAs in a variety of cell types of the developing mouse embryo. A greater understanding of where, when, and how much active exRNA is found in vivo will help broadly to direct future investigations into its potential as a carrier of cellular communication.

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Steven Mayerl - "The Measurement of Non-Homologous End Joining and Homologous Directed Recombination in a Single Reaction "
Bruce Conklin, Gladstone Institute and University of California San Francisco

Genome editing is one of the forefront topics of science with vast potential uses. One large application is the effects that precise genome editing will have on the field of regenerative medicine. Precise genome editing for therapeutic purposes is difficult to achieve because it requires the pathway of homology directed repair (HDR) to be active rather than non-homologous end joining (NHEJ) which results in deleterious insertions or deletions in the DNA. These pathways are distinct and are regulated by different enzymes. These pathways are both activated as a response to double stranded break in the genome. While NHEJ as a pathway is much more favored as a mechanism for repair we in the Srivastava/Conklin laboratories are much more interested in HDR due to its therapeutic uses. We developed an assay based on droplet digital PCR (ddPCR) to quantify HDR and NHEJ at the same time. This powerful technique allows us to use a variety of different nucleases and nickases and test each of their abilities to induce HDR while at the same time measuring the activity of NHEJ. We attempt to find the best cutting tool that will allow us to maximize the amount of HDR while at the same time minimizing the activity of NHEJ.

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Brendan Kelly - " Functional Analysis of the H3.3-K27M Mutation in Pediatric Glioma-Derived IPS Cells "
Marius Wernig, Stanford University

A heterozygous missense mutation in the H3F3A gene, which encodes a lysine-27-to-methionine substitution in the replication-independent histone H3.3, has been implicated as the main tumor driver in a subset of pediatric high-grade gliomas. This mutant histone variant, H3.3-K27M, alters normal histone marks and promotes a globally hypomethylated DNA landscape. Recent evidence has led to speculation that this mutation promotes gliomagenesis, exclusively, in oligodendrocyte progenitor cells (OPCs) to form diffuse intrinsic pontine gliomas (DIPGs). Thus, the purpose of this study is to determine the epigenetic and oncogenic properties associated with this mutation in OPCs, in order to determine if it is the main tumor driver, in this particular cell of origin. To accomplish this, three patient-derived DIPG cell lines, which exhibit the H3.3-K27M mutation, will be reprogrammed into induced pluripotent stem cells (iPSCs), in order to reverse epigenetic configurations associated with the tumors. Once this is accomplished, specifically, the mutant allele will be corrected with with a floxed-wildtype version of H3F3A attached to an inducible mutant version, via the CRISPR/Cas9 system. These iPSCs will then be differentiated into cells of the neural lineage. This confers the ability to compare, with a great degree of accuracy, the phenotypic and epigenetic differences, and the degree to which this mutation is the main promoter of oncogenic properties in cells with and without this mutation. Therefore, through directed differentiation we intend to compare iPSC derived: OPCs, neural stem cells (NSCs), and astrocyte committed progenitors (ACPs), with and without the H3.3-K27M mutation, to determine whether this mutation is oncogenic, particularly, in OPCs.

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Ian Meyers - "The role of cell polarity protein Lgl1 in oligodendrocytes precursor cells "
Claudia Petritsch, University of California, San Francisco

Lethal Giant Larvae (Lgl1) is a protein involved in establishment of cellular polarity and is implicated in numerous cancers by expression or splicing aberration. Studies in the brains of mammalian models have shown protein knockout results in lesions exhibiting overproliferation and differentiation defects reminiscent of neoplasm. Our lab is examining the role of Lgl1 in regulation of key components of tissue homeostasis with emphasis on oligodendrocyte precursors. This cell type differentiates into myelinating oligodendrocytes and constitutes the largest proliferative population of the adult brain. I am working specifically in characterizing the molecular basis of the role of Lgl1 in regulating migration and proliferation in oligodendrocyte precursors derived from the corpus callosum of adult mice. Through motility and cell cycle analysis we have shown phenotypic effect of Lgl1 ablation and are now investigating both the subcellular motor protein dynamics resultant from Lgl1 loss as well as downstream transcriptomic alteration. These studies will help define the role of Lgl1 in the migratory and proliferative oligodendrocyte mutant, and inform of mechanisms of oligodendrocyte development and how this dysfunction can potentiate disease.

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Samantha Shelton - " In Vivo Analyses of Autism Spectrum Disorder Candidate Gene CNTNAP2 in Inhibitory Cortical Interneurons"
John Rubenstein, University of California at San Francisco

Little is known about the growing number of gene mutations implicated in Autism Spectrum Disorder (ASD). Their mutations need to be studied in order to predict in vivo effects. We hypothesize that mutations found in ASD genes will cause dysregulation of GABAergic interneuron development. The aim of this project is to utilize a moderate throughput assay to identify in vivo functional changes that are caused by nonsynonymous mutations in candidate ASD genes. We will focus on CNTNAP2, an ASD susceptibility gene that has multiple mutant alleles that were identified in ASD populations. CNTNAP2 dysfunction may contribute to neuropsychiatric diseases such as ASD, schizophrenia, and epilepsy.

In order to develop an in vivo screening assay, GABAergic neural stem cells from the medial ganglionic eminence (MGE) are being utilized as a model system. The MGE has been found to produce GABAergic progenitors that migrate into the neocortex to differentiate into interneurons. These MGE cells can be easily transduced via lentiviruses and transplanted into wild type cortices to study the effect of expressing a gene in these cells as they develop. Cell autonomous functions of CNTNAP2 in developing cortical interneurons will be assessed by transducing lentiviruses that express human CNTNAP2 wild type (WT) or a CNTNAP2 mutant into MGE cells that lack the CNTNAP2 gene to assess the ability of CNTNAP2 mutants to functionally complement the CNTNAP2 loss of function phenotypes. The CNTNAP2 gene will be inserted into a lentiviral vector that includes a Dlxi12b enhancer specific to GABAergic cells of the forebrain and the minimal promoter beta globin. These elements drive expression of both GFP and CNTNAP2 within GABAergic neural precursors of the MGE. CNTNAP2 WT mice will be used as a control. Control and CNTNAP2-/- mice will be generated for MGE dissection, viral transduction, and cortical transplantation. The MGE cells that have been transduced with CNTNAP2 alleles will be studied at four developmental time points to assess migration, cell fate, cell morphology, connectivity and physiology. MGE cells obtained from embryonic day (E)12.5 will be transduced with Dlx12b-GFP-T2a-MCS lentivirus to express GFP and CNTNAP2 WT or mutant to asses the ability to rescue the lack of CNTNAP2.

This assay will be a novel way to bridge the increasing number of mutant ASD alleles being discovered in genetic screens with functional in vivo readout of allele function in mammalian neocortex. This will accelerate our ability to functionally assess if mutations enriched in ASD populations alter protein function in vivo. It will also nullify the need for time intensive and expensive knock in mouse models for each ASD mutant allele. This complementation assay can be modified to include different enhancers/promoters to study other cell types for moderate throughput region/cell-type specific in vivo screening.

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