Ngoc Nhu Tran

All Publications

• CTLA-4 Haploinsufficiency Presenting as Extensive Enteropathy in a Patient With Very Early Onset Inflammatory Bowel Disease. JPGN reports Tran, N. N., Setty, M., Cham, E., Chan, A. Y., Ali, S. 2021; 2 (3): e099

  Abstract

  Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.

  View details for DOI 10.1097/PG9.0000000000000099

  View details for PubMedID 37205940

  View details for PubMedCentralID PMC10191597

• Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. Cell reports Topol, A., Zhu, S., Hartley, B. J., English, J., Hauberg, M. E., Tran, N., Rittenhouse, C. A., Simone, A., Ruderfer, D. M., Johnson, J., Readhead, B., Hadas, Y., Gochman, P. A., Wang, Y. C., Shah, H., Cagney, G., Rapoport, J., Gage, F. H., Dudley, J. T., Sklar, P., Mattheisen, M., Cotter, D., Fang, G., Brennand, K. J. 2016; 15 (5): 1024-1036

  Abstract

  Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

  View details for DOI 10.1016/j.celrep.2016.03.090

  View details for PubMedID 27117414

  View details for PubMedCentralID PMC4856588

• Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients. Biological psychiatry Topol, A., Zhu, S., Tran, N., Simone, A., Fang, G., Brennand, K. J. 2015; 78 (6): e29-34

  View details for DOI 10.1016/j.biopsych.2014.12.028

  View details for PubMedID 25708228

  View details for PubMedCentralID PMC4520784

• Dopaminergic differentiation of schizophrenia hiPSCs. Molecular psychiatry Hartley, B. J., Tran, N., Ladran, I., Reggio, K., Brennand, K. J. 2015; 20 (5): 549-50

  View details for DOI 10.1038/mp.2014.194

  View details for PubMedID 25623947

  View details for PubMedCentralID PMC4500053

• Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular psychiatry Brennand, K., Savas, J. N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., Beaumont, K. G., Kim, H. J., Topol, A., Ladran, I., Abdelrahim, M., Matikainen-Ankney, B., Chao, S. H., Mrksich, M., Rakic, P., Fang, G., Zhang, B., Yates, J. R., Gage, F. H. 2015; 20 (3): 361-8

  Abstract

  Consistent with recent reports indicating that neurons differentiated in vitro from human-induced pluripotent stem cells (hiPSCs) are immature relative to those in the human brain, gene expression comparisons of our hiPSC-derived neurons to the Allen BrainSpan Atlas indicate that they most resemble fetal brain tissue. This finding suggests that, rather than modeling the late features of schizophrenia (SZ), hiPSC-based models may be better suited for the study of disease predisposition. We now report that a significant fraction of the gene signature of SZ hiPSC-derived neurons is conserved in SZ hiPSC neural progenitor cells (NPCs). We used two independent discovery-based approaches-microarray gene expression and stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomic mass spectrometry analyses-to identify cellular phenotypes in SZ hiPSC NPCs from four SZ patients. From our findings that SZ hiPSC NPCs show abnormal gene expression and protein levels related to cytoskeletal remodeling and oxidative stress, we predicted, and subsequently observed, aberrant migration and increased oxidative stress in SZ hiPSC NPCs. These reproducible NPC phenotypes were identified through scalable assays that can be applied to expanded cohorts of SZ patients, making them a potentially valuable tool with which to study the developmental mechanisms contributing to SZ.

  View details for DOI 10.1038/mp.2014.22

  View details for PubMedID 24686136

  View details for PubMedCentralID PMC4182344

• A guide to generating and using hiPSC derived NPCs for the study of neurological diseases. Journal of visualized experiments : JoVE Topol, A., Tran, N. N., Brennand, K. J. 2015: e52495

  Abstract

  Post-mortem studies of neurological diseases are not ideal for identifying the underlying causes of disease initiation, as many diseases include a long period of disease progression prior to the onset of symptoms. Because fibroblasts from patients and healthy controls can be efficiently reprogrammed into human induced pluripotent stem cells (hiPSCs), and subsequently differentiated into neural progenitor cells (NPCs) and neurons for the study of these diseases, it is now possible to recapitulate the developmental events that occurred prior to symptom onset in patients. We present a method by which to efficiently differentiate hiPSCs into NPCs, which in addition to being capable of further differentiation into functional neurons, can also be robustly passaged, freeze-thawed or transitioned to grow as neurospheres, enabling rapid genetic screening to identify the molecular factors that impact cellular phenotypes including replication, migration, oxidative stress and/or apoptosis. Patient derived hiPSC NPCs are a unique platform, ideally suited for the empirical testing of the cellular or molecular consequences of manipulating gene expression.

  View details for DOI 10.3791/52495

  View details for PubMedID 25742222

  View details for PubMedCentralID PMC4354663

• Neural stem and progenitor cells in health and disease. Wiley interdisciplinary reviews. Systems biology and medicine Ladran, I., Tran, N., Topol, A., Brennand, K. J. 2013; 5 (6): 701-15

  Abstract

  Neural stem/progenitor cells (NSPCs) have the potential to differentiate into neurons, astrocytes, and/or oligodendrocytes. Because these cells can be expanded in culture, they represent a vast source of neural cells. With the recent discovery that patient fibroblasts can be reprogrammed directly into induced NSPCs, the regulation of NSPC fate and function, in the context of cell-based disease models and patient-specific cell-replacement therapies, warrants review.

  View details for DOI 10.1002/wsbm.1239

  View details for PubMedID 24068527

  View details for PubMedCentralID PMC4160040

• Modeling schizophrenia using induced pluripotent stem cell-derived and fibroblast-induced neurons. Schizophrenia bulletin Tran, N. N., Ladran, I. G., Brennand, K. J. 2013; 39 (1): 4-10

  Abstract

  Although schizophrenia affects a number of brain regions and produces a range of clinical symptoms, we believe its origins lie at the level of single neurons and simple networks. Owing to this, as well as to its high degree of heritability, we hypothesize that schizophrenia is amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or fibroblast-induced neurons, a limitless quantity of live human neurons can now be generated from patient skin biopsies. We predict that cell-based studies will ultimately contribute to our understanding of the molecular and cellular underpinnings of this debilitating disorder.

  View details for DOI 10.1093/schbul/sbs127

  View details for PubMedID 23172000

  View details for PubMedCentralID PMC3523925

• Modeling psychiatric disorders at the cellular and network levels. Molecular psychiatry Brennand, K. J., Simone, A., Tran, N., Gage, F. H. 2012; 17 (12): 1239-53

  Abstract

  Although psychiatric disorders such as autism spectrum disorders, schizophrenia and bipolar disorder affect a number of brain regions and produce a complex array of clinical symptoms, basic phenotypes likely exist at the level of single neurons and simple networks. Being highly heritable, it is hypothesized that these disorders are amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or induced neurons from fibroblasts, limitless numbers of live human neurons can now be generated from patients with a genetic background permissive to the disease state. We predict that cell-based studies will ultimately contribute to our understanding of the initiation, progression and treatment of these psychiatric disorders.

  View details for DOI 10.1038/mp.2012.20

  View details for PubMedID 22472874

  View details for PubMedCentralID PMC3465628

• Modelling schizophrenia using human induced pluripotent stem cells. Nature Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., McCarthy, S., Sebat, J., Gage, F. H. 2011; 473 (7346): 221-5

  Abstract

  Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

  View details for DOI 10.1038/nature09915

  View details for PubMedID 21490598

  View details for PubMedCentralID PMC3392969