Black Family Stem Cell Institute

Translational and Clinical Research

From a grandmother struggling with Parkinson’s disease to a teenager dealing with schizophrenia, there are countless patients trying to manage a range of conditions with currently available therapies—and those therapies just aren’t good enough.

The scientists at the Black Family Stem Cell Institute are working to translate our findings into tomorrow’s newest treatments. Through clinical trials, we not only bring the benefits of our work to the patients who most need them, but we also gather data and insights necessary to take our science to the next level.

For us, the success of our research isn’t measured under a microscope. It’s measured by the stronger heartbeat of a cardiac patient, the cancer patient whose disease is in remission, and the daily activities that countless others enjoy as a result of the new therapies that finally enable them to move beyond their disease.

Investigators with a major focus in translational and clinical research include:

Tim D. Ahfeldt, PhD

Tim Ahfeldt, PhD, is an Assistant Professor in the Nash Family Department of Neuroscience at the Icahn School of Medicine at Mount Sinai, the Ronald M. Loeb Center for Alzheimer’s disease, and The Friedman Brain Institute. Dr. Ahfeldt’s research asks why some cells are more vulnerable to neurodegenerative disease than others. Developing new tools to address this question will aid us in understanding pathological mechanisms and advancing pharmacological interventions. Human pluripotent stem cells (hPSCs), which can be differentiated into all cell types, provide an unparalleled system for studying human neurodegenerative diseases in vitro. For example, Parkinson’s disease (PD) is characterized by the almost complete loss of midbrain dopaminergic neurons in the substantia nigra pars compacta, while the closest relatives in the ventral tegmental area are relatively spared. Using CRISPR gene editing techniques, we have developed several isogenic hPSCs models of PD. Our data suggest that our PD model recapitulates disease aspects found in vivo as we observe selective vulnerability in differentiated midbrain dopaminergic neurons in PD lines, providing us with an opportunity to address the question of specific cell type vulnerability in a novel way.

Ongoing research interests include:

  • Determining how disease genotype impacts phenotype and affects specific cell-types
  • Identifying disease relevant common and unique pathways in order to uncover new therapeutic targets

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James J. Bieker, PhD

James J. Bieker, PhD, is a Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. The laboratory's interest is in the transcriptional regulation of red blood cell-specific gene expression, and in identifying the molecular events that confer the ability to express lineage-specific genes in uncommitted, pluripotent hematopoietic stem cells. These issues are being addressed by the functional analysis of a novel, erythroid-specific gene that the Bieker Laboratory identified a number of years ago named erythroid Krüppel-like factor; EKLF. Biochemical, molecular, cellular, developmental, and genetic studies in mice and humans have established that EKLF is an essential component required for globin switching and completion of the definitive erythroid program.

Using our model system, we aim to disentangle genotype from phenotype and cell-type and identify disease relevant common and unique pathways that hold promise for future therapies.

Ongoing research interests include:

  • Analyzing EKLF protein/protein interactions and how they result in altered transcriptional and epigenetic changes at target loci
  • Determining how molecular controls converge to regulate late events in erythropoiesis, particularly enucleation
  • Analyzing EKLF upstream regulators to explain its exquisite tissue-restricted expression pattern, and to possibly link alteration of its expression level to aberrant red cell biology
  • Determining the mechanism by which a human mutation in EKLF leads to congenital dyserythropoietic anemia.

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Timothy A. Blenkinsop, PhD

Timothy A. Blenkinsop, PhD, is an Assistant Professor in the Department of Cell, Development, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, as well as member of the Ophthalmology Department, the Black Family Stem Cell Institute, and Mount Sinai’s Eye and Vision Research Institute. His team is interested in understanding human retina development in normal and pathological situations, as well as in modeling in vitro various eye diseases. The lab’s primary interest lies in retina stem cell biology, cell replacement therapy, and endogenous retina regeneration potential. The lab uses adult human tissues and pluripotent stem cells-derived differentiated cells to probe retina physiology and model diseases such as age-related macular degeneration, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. The main goal is to identify epigenetic regulation of cell plasticity for stimulating it with therapeutic benefit, while also modeling diseases where plasticity leads to disease.

Ongoing research interests include:

  • Exploring signaling transduction pathways involved in retinal pigment epithelium plasticity
  • Exploring cell replacement therapy for age-related macular degeneration
  • Researching cell fate specification of developing human eye field

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Kristen Brennand, PhD

Kristen Brennand, PhD, is an Associate Professor of Genetics and Genomics, Neuroscience, and Psychiatry at the Icahn School of Medicine at Mount Sinai. She trained in developmental and stem cell biology at Harvard University and in neuroscience during her postdoctoral studies at the Salk Institute for Biological Studies. By blending expertise in stem cell biology and neurobiology, she has pioneered a new approach to study psychiatric disease. By developing a G16 based model for the study of predisposition to neuropsychiatric disease, and combining it with CRISPR-based genomic engineering, the Brennand Laboratory has established a new approach by which to systematically test the impact of causal variants in human cells. The future of psychiatry requires a model of precision medicine, in which doctors consider how the patient’s genetic variants—and the many interactions among them—affect disease course and treatment response before prescribing any medication.

Ongoing research interests include:

  • Understanding the genetic mechanisms underlying schizophrenia
  • Developing personalized screening platforms to identify new therapeutics for the treatment of this debilitating disorder

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Nicole C. Dubois, PhD

Nicole Dubois, PhD, received her PhD in Cell and Developmental Biology from the Swiss Institute for Experimental Cancer Research and the University of Lausanne with Andreas Trumpp, PhD. She did her postdoctoral training in the laboratory of Gordon Keller, PhD, at the University Health Network in Toronto with a focus on pluripotent stem cell biology and their differentiation to cardiovascular lineages. She is currently an Associate Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, the Black Family Stem Cell Institute, and the Mindich Child Health and Development Institute. Dr. Dubois' group studies early heart development and congenital heart disease using pluripotent stem cell differentiations and the mouse embryo as model systems.

Ongoing research interests include:

  • Understanding the molecular mechanisms of atrial-ventricular development
  • Exploring pluripotent stem cell differentiation to cardiovascular lineages
  • Looking at cardiac maturation and tissue engineering
  • Investigating long non-coding RNAs during cardiac development
  • Exploring cardiac toxicity of cancer drugs (LINCS project)

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Bruce D. Gelb, MD

Bruce Gelb, MD, is the Gogel Family Professor of Child Health and Development and Professor of Pediatrics and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, and he directs the Mindich Child Health and Development Institute. He is a co-leader of a National Heart, Lung, and Blood Institute-funded training program in molecular and cellular cardiology. Dr. Gelb’s research group studies the genetic causes of cardiovascular diseases of childhood, particularly focusing on congenital heart defects and inherited disorders of the Ras/microtubule-associated protein (MAP) kinase signal transduction pathway (called RASopathies). His group, working with the then Black Family Stem Cell Institute Director, Ihor Lemischka, PhD, generated the first human induced pluripotent stem cell (hiPSC) model of a cardiovascular trait (hypertrophic cardiomyopathy for Noonan syndrome with multiple lentigines).

Ongoing research interests include:

  • Understanding the pathogenesis of hypertrophic cardiomyopathy for RASopathies
  • Discovering novel therapies for hypertrophic cardiomyopathy for RASopathies
  • Understanding congenital heart defect pathogenesis due to histone modifier mutations

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Saghi Ghaffari, MD, PhD, is a Professor of Cell, Developmental, and Regenerative Biology and a member of The Tisch Cancer Institute. Her lab studies mechanisms that sustain blood forming stem and progenitor cells (HSPCs) throughout life and that are perturbed in disease. Her team is particularly interested in programs that maintain quiescence of blood-forming stem cells, a property that determines the potency and overall regenerative capacity of adult stem cells and that is lost with age. Quiescence is also a mechanism by which malignant stem cells resist therapy. To attain this goal, the Ghaffari Laboratory has been investigating metabolic and mitochondrial-related programs and organelle communications in young and aged HSPCs. The Ghaffari lab uses a variety of approaches, including various omics, super resolution imaging, and gene modulation technology combined with genetically modified mouse models and human cells to address these questions.

Ongoing research interests include:

  • Investigating mechanisms that control mitochondria-lysosome communication in normal mouse and human hematopoietic stem cells (HSCs) in aged HSCs and in leukemic stem cells
  • Exploring transcriptional and epigenetic programs that regulate organelle biogenesis in HSPCs and their alteration with age
  • Investigating metabolic and redox regulation of erythroid cell maturation and identifying mechanisms and components of mitochondria-nucleus communication during this process
  • Elucidating mechanisms of apoptosis in beta-thalassemia

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Ronald Hoffman, MD, is the Albert A. and Vera G. List Professor of Medicine at the Icahn School of Medicine at Mount Sinai. He is a member of The Tisch Cancer Institute. His team has two areas of interest. One deals with the expansion of the number of marrow repopulating cells present in cord blood for transplantation into humans undergoing allogeneic stem cell transplantation for refractory hematological malignancies. This expansion strategy uses histone deacetylase inhibitors. The team is attempting to understand the mechanism underlying this ex vivo stem cell expansion technology, and is actively evaluating the clinical potential of this expanded cell product in a phase I clinical trial. The second area of interest deals with the blood cancer myelofibrosis. Dr. Hoffman and his team are characterizing the malignant myelofibrosis stem cells and their progeny and the consequence of their interactions with the marrow and splenic microenvironments. With this growing body of information the group is identifying novel agents to deplete myelofibrosis stem cells. These agents are currently being evaluated in a series of phase I/II clinical trials in a clinical consortium including 11 institutions in the United States and Canada, headed by Dr. Hoffman.

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Kateri Moore, DVM

Kateri Moore, DVM, is a Professor in Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai and a member of The Tisch Cancer Institute. Her research is focused on both normal and reprogrammed hematopoietic stem cells (HSCs). To study normal hematopoiesis, she uses mouse models that allow her to define the characteristics of temporally defined quiescent HSCs during homeostasis. She researches perturbed hematopoiesis and aging HSCs using this model. These studies have implications for understanding the ability of leukemic stem cells and other tumor initiating cells to mimic normal stem cells and remain quiescent, thus evading current therapies. Her lab has reported direct reprogramming of mouse and human fibroblasts into hematopoietic cells using transcription factors. Insights gained during the reprogramming studies have led to the prospective isolation of the immediate precursor cell that give rise to definitive HSC during embryonic development. These studies have broad applications to cancers of the blood and immune system and others that require a stem cell transplant.

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Eirini Papapetrou, MD, PhD

Eirini Papapetrou, MD, PhD, is an Associate Professor of Oncological Sciences, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai; and Associate Director of the Pluripotent Stem Cell Engineering Core. Her laboratory pioneered the modeling of blood cancers with human-induced pluripotent stem cell (iPSC). Specifically, her lab developed the first iPSC models of myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia by reprogramming patient cells and by correcting and introducing mutations using CRISPR/Cas9-mediated gene editing. Dr. Papapetrou’s research program combines techniques and principles from stem cell research, cancer biology, and hematopoiesis with the goal of understanding disease mechanisms and identifying new therapeutic targets for hematologic malignancies. The unifying theme of the lab’s projects is the creation of genetically precise isogenic iPSC models of myeloid cancers and exploitation of the unique capabilities they offer for genotype-to-phenotype studies, interrogation of the effects of oncogenic mutations with integrative genomics analyses in a faithful cellular and genomic environment and genetic (CRISPR), and small molecule screens for drug repurposing or drug discovery. Dr. Papapetrou is the recipient of several awards, including the American Society of Gene and Cell Therapy Outstanding New Investigator Award, Damon Runyon-Rachleff Innovation Award, American Society of Hematology Scholar Award, Pershing Square Sohn Prize, and Leukemia and Lymphoma Society Scholar award, among others. She is an elected member of the American Society for Clinical Investigation.

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Christoph Schaniel, PhD

Christoph Schaniel, PhD, is an Assistant Professor in the Department of Pharmacological Sciences, the Department of Cell, Developmental and Regenerative Biology, and a member of the Mount Sinai Institute for System Biomedicine. His research is centered on understanding the cellular and molecular nature of hematopoietic stem cells (HSCs) in health and disease. He helped develop a clinical ex vivo expansion and cryopreservation process of umbilical cord blood HSCs for allogenic stem cell transplantation in refractory hematological malignancies that is being evaluated in a clinical trial (in collaboration with Ronald Hoffman, MD, and Camelia Iancu-Rubin, PhD). Additionally, he is investigating the mechanism and clinical applicability of direct reprogramming of HSCs from somatic cells for cell replacement therapies (together with Kateri A. Moore, DVM). Other research focuses on the effect of valproic acid on normal vs. malignant HSCs, the underlying pathologies of hematological malignancies and cancers using human primary stem cells, and induced pluripotent stem cells (PSCs). He is also invested in various projects aimed at understanding the mechanisms of cardiovascular diseases and drug action, responses, and toxicity in individuals using induced PSCs with the goal of advancing and developing precise and personalized therapeutic treatments.

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Nan Yang, PhD

Nan Yang, PhD, is an Assistant Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai. She is also a member of The Friedman Brain Institute, and the Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai. She pioneered the work in direct lineage reprogramming from somatic cells to neural cells and its application in neuropsychiatric and neurological disease modeling. Her team studies how disease-associated risk variants contribute to pathogenesis of multiple neuropsychiatric disorders with a particular focus on understanding how patient mutations in chromatin modifying proteins and functional non-coding elements impact gene expression regulation and neuronal function and contribute to autism spectrum disorder (ASD).

 

Ongoing research interests include:

  • Modeling ASD mutations in chromatin factors by directed differentiation protocols of human pluripotent stem cells into neurons
  • Understanding the role of the epigenome and non-coding DNA elements in neuronal signaling dependent gene regulation in different human neuronal subtypes
  • Exploring the mechanisms underlying transcription factors directed differentiation of human stem cells to neuronal subtypes.
  • Investigating autophage in human neurons and assessing functional outcome of mutations in Alzheimer's disease and Parkinson’s disease that affect autophage pathways.

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Lior Zangi, PhD

Lior Zangi, PhD, is an Assistant Professor in Cardiology at the Icahn School of Medicine at Mount Sinai. He completed his education and training at the Weizmann Institute of Science and at Harvard University. He has established a new method, mRNA based, for gene delivery to promote cardiovascular regeneration. Dr. Zangi’s laboratory investigates cellular and organ level regenerative mechanisms that can contribute to new therapeutic approaches to repair and regenerate the heart following myocardial infarction. The Zangi lab's goal is to induce cardiac regeneration after myocardial infarction using a gene therapy approach with modified mRNA. Modified mRNA is an attractive and novel in vivo gene delivery method that allows high gene expression in a variety of organs, including the heart. The Zangi Laboratory will use modified mRNA to transiently change the non-regenerative gene expression profile of adult cardiac muscle to grant regenerative capacity to the adult heart after injury. The lab plans to investigate specific genes or signaling networks on both cellular (cell specific) and tissue (whole muscle) levels, using modified mRNA and other gene delivery approaches.

Ongoing research interests include:

  • Induce cardiomyocytes proliferation and survival by manipulating cardiomyocytes metabolic pathways
  • Use cardiac reprograming to induce cardiovascular regeneration
  • Employ long non-coding RNA to induce cardiac regeneration

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Zwaka headshot

The Zwaka Lab’s main line of research investigates ways to direct pluripotent stem cells to replace human cells affected by injury or disease. Dr. Zwaka was recruited to Mount Sinai in 2013 to become Professor of Developmental and Regenerative Biology. After earning his MD and PhD degrees from Ulm University in Germany, Dr. Zwaka trained as a cardiologist and discovered the link between C-reactive protein and atherosclerotic inflammation, a connection that has had enormous importance for cardiology. Dr. Zwaka then went to the University of Wisconsin to do his postdoctoral fellowship in the lab of Jamie Thomson, who derived the first human embryonic stem cell line in 1998. In Thomson’s lab, Dr. Zwaka pioneered methods to genetically manipulate stem cells (gene editing). He then joined the faculty of Baylor College of Medicine, serving in both the Department of Molecular and Cellular Biology and in the Center for Cell and Gene Therapy. At Baylor, the Zwaka Lab discovered a key regulator of pluripotency that behaved so differently from canonical stem cell factors that it was named Ronin.

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