Andre Berndt, PhD (Bioengineering)
It is crucial to untangle the incredible complexity of the human brain in order to develop more effective therapies for neurological disorders such as autism, schizophrenia or depression. The Berndt lab designs biosensors which detect even small imbalances in neuronal function which will provide key knowledge about the underlying causes of those diseases. We develop fluorescent sensors for neurotransmitter, neuromodulators, hormones, ions and intracellular signaling molecules. The goal of our research is to provide multidimensional real-time data of neuronal activity in brains of moving and behaving animals. One big advantage is that our sensors are protein based which means they can be expressed in virtually any cell type by using virus or plasmid DNA. Thus, they are universally applicable and we seek to expand applications into other cell types such as cardiac, pancreatic or stem cells.
Mark Bothwell, PhD (Physiology and Biophysics)
Our research focuses on receptor signal transduction in the brain, in embryonic development and in neurodegenerative diseases. Areas of special interest include neurotrophin receptor function, function of the beta amyloid precursor protein, and the function of primary cilia and the neural stem cell marker Prominin-1 in neural stem cells.
Eliot Brenowitz, PhD (Psychology and Biology)
My lab studies the birth and incorporation of new neurons in the brains of adult songbirds. New neurons continue to be recruited widely throughout the forebrain of adult birds. In HVC, a region of the forebrain that regulates learned song behavior, there are pronounced seasonal changes in the total number of neurons that are driven by changes in circulating steroid hormone levels and reflect seasonal changes in the rates of neuronal birth and death. Both the division of stem cells in the ventricular zone and the recruitment of differentiated neurons to HVC vary seasonally. We are interested in how hormones act on gene expression and electrical activity of cells to regulate neurogenesis, and the functional significance of this striking form of adult brain plasticity.
Stanley Froehner, PhD (Physiology and Biophysics)
Our lab studies the muscular dystrophies, diseases that cause muscle degeneration. Our major focus is the most prevalent and severe muscular dystrophy, Duchenne Muscular Dystrophy. DMD is an X-linked inherited disease that occurs in approximately 1/5000 male births. DMD boys are diagnosed at age 2-3. Their mobility declines to the extent that most are in wheelchairs by age 10-15. Cardiomyopathy becomes a problem in their 20s and most DMD boys die in their late 20s and early 30s. Currently, there is no treatment for this devastating disease.
The cause of DMD is mutations in the dystrophin gene, one of the largest genes in the human genome. Dystrophin is a very large protein (427 kDa) localized on the sarcolemma of skeletal cardiac muscle. For gene therapy, the dystrophin cDNA is far too large to fit into AAV. Current trials are using a micro-dystrophin that encodes only about 20% of the protein. Micro-dystrophins improve the dystrophic phenotype in the mdx mouse model of DMD, but recent clinical trials do not appear to improve muscle function in DMD boys.
We have developed a non-viral platform that targets genes to skeletal and cardiac muscle. Our platform has several important advantages over AAV. Our platform can deliver genes of any size. Also, the genes can be delivered more than once (a major limitation of AAV). Finally, toxicity problems encountered with high doses of AAV required for skeletal muscle are avoided with our platform. Non-viral delivery of full-length dystrophin would be a major step toward treatment of this devastating disease. Our non-viral platform will revolutionize gene therapy in skeletal and cardiac muscle diseases.
Suman Jayadev, MD (Neurology)
Our laboratory is interested in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. As a Neurogenetics laboratory, we study the cellular mechanisms of multiple central nervous cell types differentiated from stem cells derived from patients with monogenic causes of neurodegenerative diseases such as Alzheimer disease and ALS.
George Kraft, MD, MS (Rehabilitation Medicine and Neurology)
Multiple sclerosis is an immune-mediated disease. In the late-1990s I, as director of the UW MS Center, collaborated with Dr. Keith Sullivan in developing a research plan to treat patients with MS by 1) harvesting and cryopreserving their blood stem cells, 2) suppressing their immune system using irradiation, chemotherapy, and immunotherapy. And 3) “rescuing” the patients by infusing their blood stem cells back into their bodies. Since then, we have refined the treatment and made it more effective and less toxic to their bodies by eliminating the irradiation and reducing the toxicity of the chemotherapy. We have now completed the third 5 year protocol, demonstrating that this is a very effective and well tolerated treatment in well- chosen patients.
David Marcinek, PhD (Radiology)
The overriding theme of research in our lab is the interaction between mitochondria and cell stress and its effect on the pathology of chronic disease and aging. Most people learn about mitochondria as kidney bean shaped structures that function as the “Powerhouse of the Cell” by generating chemical energy in the form of ATP. However, mitochondria are actually structurally and functionally dynamic organelles that sit at the nexus between cell energetics, redox biology, and cell signaling. As a result, mitochondrial biology controls many aspects of cell function and plays a critical role in cell, tissue, and organismal responses to acute and chronic stressors. Our interest in muscle satellite cells and regeneration is relatively new and came about as we became interested in the role mitochondrial play in muscle injury and recovery. The two main questions that drive most of our research are:
1) What are the structural changes that lead to increased mitochondrial redox stress with chronic disease?
2) Why does increased mitochondria redox stress translate to cell pathology in some circumstance and adaptive responses in others?
The second question has led us to start collaborations with other ISCRM labs to better understand how changes in mitochondrial function with age and chronic disease alter the ability of muscle satellite cells to respond to stimuli. Answering these questions will improve our understanding the role of mitochondria in disease to help develop targeted interventions to improve quality of life with age and chronic disease.
Ghayda Mirzaa, MD (Pediatrics)
The broad goal of our research is to understand the causes, mechanisms and outcomes of human developmental brain disorders, including brain growth abnormalities (megalencephaly, microcephaly), malformations of cortical development and associated co-morbidities including autism, epilepsy and intellectual disability. Our work has led to gene discovery for several disorders associated with brain growth dysregulation including megalencephaly (e.g. PIK3CA, PIK3R2, AKT3, MTOR, CCND2) and microcephaly (e.g. STAMBP, CENPE, KIF11, CDC42), among several others (Mirzaa et al., Neuropediatrics 2004; Mirzaa et al., AJMG 2012; McDonnell et al., Nature Genetics 2013; Mirzaa et al., Pediatric Neurology 2013; Mirzaa et al., Human Genetics 2014; Martinelli et al., American Journal of Human Genetics 2018). Our work on the PI3K-AKT-MTOR related brain overgrowth disorders has led to the identification of several genes within this pathway that cause brain growth dysregulation and focal cortical dysplasia, with important therapeutic implications using PI3K-AKT-MTOR pathway inhibitors (Rivière et al., Nature Genetics 2012; Mirzaa et al., Nature Genetics 2014; Jansen et al., Brain 2015; Mirzaa et al., Lancet Neurology, 2015; Mirzaa et al., JAMA Neurology, 2016).
Our lab is focused on identifying the molecular and cellular mechanisms of developmental brain disorders and translating these genomic discoveries to molecularly-guided therapies using high throughput genomic, transcriptomic, and proteomic methods in relevant human tissues, combined with functional validation of genetic variants using human reprogramming and genome editing via CRISPR-Cas9 methods. Our lab houses the first human stem cell tissue culture facility at the Seattle Children’s Research Institute (SCRI) solely dedicated to generating human induced Pluripotent Stem Cells (iPSCs), Neural Progenitor cells (NPCs), cortical neurons and cerebral organoids to model genetic variants that are of high relevance to neurodevelopmental disorders, and to be used as a platform for future pre-clinical high throughput drug screening.
Anna Naumova, PhD (Radiology)
I have a long-standing interest to scientific research, biomedical imaging and data analytics. The main focus of my research is advancing pre-clinical and clinical cardiovascular studies at the University of Washington by implementation of the state-of-the-art non-invasive imaging technology for assessment of heart physiology, pathophysiology, myocardial perfusion and tissue composition. Specifically, I am interested in heart regeneration with human cardiomyocytes and non-invasive imaging of transplanted cells. We are developing quantitative non-contrast MRI techniques for characterization of myocardial tissue composition. This would allow identification of the fibrotic areas and myocardial graft without need of the MRI contrast agents. Our imaging approach is suitable to clinical studies on patients.
David W. Raible, PhD (Biological Structure)
We are interested in the development of the peripheral nervous system using zebrafish as a model. Current research focuses on two areas: sensory neurons derived from neural crest and the mechanosensory lateral line system.
Wendy H. Raskind, MD, PhD (Medical Genetics, Psychiatry and Behavioral Sciences)
Our laboratory studies the genetics of neurobehavioral and neurodegenerative disorders. One focus is neurologic diseases caused by mutations in single genes. Examples of these disorders include cerebellar ataxias, spasticity, movement disorders, neuropathies and myopathies. A second main area of interest is the genetic basis of common and complex disorders, including dyslexia, autism, and Alzheimer’s disease. We and other researchers have identified genes and mutations that contribute to some of these disorders. We are generating neuron cells from stem cells derived from patients with an unusual form of Parkinson’s disease so that we can study the steps that occur in the brain as the disease progresses.
Jeff Rasmussen, PhD (Biology)
Our lab uses zebrafish to gain insights into neuronal and tissue plasticity, both during development and following injury. The skin is our largest sensory organ and is densely innervated by somatosensory nerve endings that sense pain and touch. Nerve regeneration is often incomplete following skin injury, and sensory loss is a major complication associated with diabetes and chemotherapy. Using the imaging advantages of the zebrafish system and novel remodeling assays developed in the lab, we have identified interactions between somatosensory nerve endings and several specialized cell types (including osteoblasts, resident macrophages, and sensory cells) within the skin tissue environment. Our long-term goals are to understand: (1) the molecular basis for these axon-tissue interactions; and (2) how these interactions regulate tissue form and function, both during development and in disease states.
Alec Smith, PhD (Physiology & Biophysics)
My lab’s research is focused on understanding the mechanistic pathways that underpin muscle and nervous tissue development in health and disease. To achieve this, we are developing human stem cell-derived models of neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS). By analyzing the behavior of these cells, we aim to better define how the causal mutation leads to the development and progression of neurodegenerative disease. Ultimately, identification of pathways critical to disease progression will provide new targets for therapeutic intervention, leading to the development of new treatments for patients suffering from these debilitating and life-threatening conditions.
Daniel Storm, PhD (Pharmacology)
These groups are engaged in experiments where they are injecting neuronal precursor cells into the hippocampus to examine cell fate, functional integration, and survival. These studies have obvious clinical potential because they may lead to new strategies to treat neurodegenerative diseases including Alzheimer’s, Parkinson’s and various forms of mental retardation by stereotaxic injection of neuronal precursor cells into specific areas of human brain.
The research proposed by the Storm/Xia labs is unique and is unlikely to be duplicated at another University because it is based on technology only available through collaborative efforts between the labs. Specifically, we are carrying out experiments in which we inject neuronal precursor cells into the hippocampus of mice. Our objectives are to determine if injected neuronal precursor cells differentiate in vivo, and are functionally integrated into the circuitry. If we accomplish this goal, we should be able to inject cells into the hippocampus that are expressing specific gene products that can affect the physiology of brain and correct defects associated with various diseases including neurodegenerative diseases. This project is based upon the Xia labs expertise in growing neuronal precursor cells and their technology to transfect and express gene products in these cells. This collaboration also relies on the ability of the Storm lab to determine if injected cells become functionally incorporated into hippocampal circuits during memory formation and to inject cells stereotactically into mouse brain. I know of no other University where this combination of technology exists.
Valeri Vasioukhin, PhD (Fred Hutch)
Our laboratory studies the mechanisms and significance of cell polarity and cell adhesion in normal mammalian development and cancer.
Zhengui Xia, PhD (Environmental Health)
One of our research interests is to elucidate signal transduction mechanisms that regulate the fate of neural stem cells, i.e. what makes a neural stem cell proliferate and differentiate into neurons or glia in the mammalian brain. We are interested in neural stem cell regulation both during development and in adult neurogenesis. Specifically, recent studies in our lab suggest a novel role for the extracellular-signal-regulated kinase 5 (ERK5) MAP kinase in regulating the fate choice of cortical stem cells during development. The elucidation of molecular mechanisms that regulate neural progenitor cell proliferation and differentiation is important for an understanding of neural developmental and neurodegenerative diseases. Furthermore, stem cell-based cell replacement therapy offers enormous potential for the treatment of a variety of developmental, psychiatric, neurodegenerative and aging related diseases for which there are currently no cures. Moreover, environmental toxicants may cause developmental neurotoxicity by perturbing these signaling mechanisms that regulate neurogenesis.
Our laboratory is also interested in molecular mechanisms and signal transduction pathways that regulate neuronal survival and cell death. It has become increasingly evident that many environmental toxicants might contribute to the development of neurodegenerative disorders including Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. Our recent effort has focused on elucidating signaling mechanisms that regulate dopaminergic neuron cell death in relation to Parkinson’s disease using exposure to several pesticides as model systems. It is our hope that these mechanistic studies may ultimately lead to the development of pharmacological interventions and clinical strategies for treatment of Parkinson’s disease. These studies may also provide insights concerning the relationships between environmental toxicants and the etiology of neurodegenerative disorders.
Smita Yadav, PhD (Pharmacology)
The Yadav laboratory is interested in investigating kinase signaling pathways that are important for neuronal development as well as in understanding how their dysfunction leads to neurodevelopmental and psychiatric disorders such as autism and schizophrenia. Our lab utilizes a combination of powerful approaches in induced pluripotent stem cell (iPSC) technology, chemical-genetics, high-resolution live cell imaging and quantitative proteomics to investigate the role of kinases and their downstream targets in development and neurodevelopmental disease.
Jessica E. Young, PhD (Pathology)
Alzheimer’s disease is the most common neurodegenerative disorder. The main interest of the Young Lab is to determine the molecular and cellular mechanisms behind genetic risk for late-onset sporadic Alzheimer’s disease (SAD). Human induced pluripotent stem cells (hiPSCs) are a powerful way to study SAD because the genetic background of an individual patient can be captured in a dish. Every one of us harbors variants in our genome that predispose to or protect from SAD risk. How combinations of genetic variants lead to disease in some individuals but not in others is unknown. We differentiate hiPSCs from SAD patients and healthy controls into human neurons in order to understand how genetic background contributes to SAD phenotypes that can be measured in the laboratory.
Current projects are focused on:
Our work will contribute to basic understanding of neuronal mechanisms that become dysfunctional in SAD as well as open up new avenues to test for therapy development.