Black Family Stem Cell Institute

Brain Diseases

Genetic studies increasingly demonstrate that brain disease is highly heritable, and that it can arise as a result of a growing number of rare and common genetic variants.

It is critical that we unravel how these many risk factors interact within and between the diverse cell types populating the brain. By developing human induced pluripotent stem cell (hiPSC)-based models for the study of predisposition to neurodegenerative and psychiatric diseases, we have established new platforms by which to systematically test the impact of causal variants in human cells.  We are moving towards a model of precision medicine, wherein each patient’s genetic variants, and interactions between them, can predict disease trajectory and potential therapeutic interventions.

Laboratories in the Black Family Stem Cell Institute study a variety of human brain diseases, from autism spectrum disorder and schizophrenia to Alzheimer’s disease and Parkinson’s disease. Our goal is to better understand the distinct genetic, epigenetic, and environmental risk factors that predispose us to some diseases and confer resilience to others. Our highly collaborative work involves integrating advanced neurogenetic and epigenetic studies, rigorously characterized clinical cohorts, and hiPSC-based analyses, allowing us to move seamlessly between large-scale clinical datasets and isogenic functional evaluations.

Investigators with a major focus in neurodegenerative diseases 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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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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Marion Dejosez, PhD

Marion Dejosez, PhD, is an Assistant Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. She serves as Associate Director for the Huffington Center for Cell-Based Research in Parkinson’s Disease. Dr. Dejosez obtained her master’s degree in genetics from the University of Cologne and her PhD in cancer biology from the University of Dusseldorf. She trained as a postdoctoral fellow at the Center for Gene and Cell Therapy at Baylor College of Medicine in stem cell biology. During this time she discovered Ronin, a novel factor essential for embryogenesis and ES cell pluripotency (Cell, 2008, G&D 2010). She became an Assistant Professor in the Department of Molecular and Human Genetics in 2008 and subsequently directed the Stem Cell Core Facility at Baylor. In collaboration with the Zwaka Laboratory. She identified genes that safeguard stem cell growth in mouse embryogenesis (Science, 2013). She joined the faculty of Mount Sinai in 2013 where her studies continued to focus on understanding the molecular mechanisms that underlie embryonic stem cell pluripotency, self-renewal, and differentiation, with special emphasis on hematopoiesis and neurogenesis. Her research seeks to identify pathways that contribute to stem cell identity, and to understand their importance in tissue homeostasis and disease.

Ongoing research interests include:

  • Exploring Ronin’s contribution to genome organization in stem cells and their derivatives
  • Investigating Ronin’s function in hematopoiesis
  • Understanding the molecular mechanisms that contribute to neurodegenerative, diseases including ataxia and Parkinson’s disease using brain organoid and mouse models

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Samuele G. Marro

Samuele G. Marro, PhD, is an Assistant Professor in the Nash Family Department of Neuroscience and co-Director of the Stem Cell Engineering Core at the Icahn School of Medicine at Mount Sinai. His research team focuses on the regulation of synaptic plasticity and its dysfunction in Fragile X syndrome, the number one genetic cause of autism. To accomplish this, the group studies human neurons directly differentiated from pluripotent stem cells that are genetically modified using CRISPR/Cas9 tools. The institutional Stem Cell Engineering Core itself provides services and resources at a reduced cost to the Icahn School of Medicine community that include the derivation of iPS from patient blood samples; iPS differentiation into different cell types; and gene-editing to create or repair putative disease mutations.

      

Ongoing research interests include:

  • Investigating protein homeostasis in human neurons
  • Exploring epigenetic regulation of synaptic plasticity
  • Understanding and correcting the epigenetic silencing in Fragile X syndrome

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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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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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