ISCRM

Central Nervous System

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.

Robert Hevner (Pathology)
My interest in stem cells has grown from my core interest in genetic mechanisms of brain development. To explore similarities between development and adult neurogenesis, my lab has recently studied expression of developmental transcription factors in adult hippocampal neurogenesis. Remarkably, we are finding that the same transcription factors are expressed, in the same sequence, in adult neurogenesis as in the embryonic cerebral cortex. We believe that these genes specify key aspects of neural cell fate, and that stem cells may ultimately be guided to differentiate along desired lines by inducing the appropriate transcription factors. Thus, we hope to learn to "instruct" neural stem cells to generate the appropriate axonal connections, neurotransmitters, dendritic structures, and physiological properties to repair injured circuits efficiently.

Philip Horner, PhD (Neurological Surgery)
This lab is focused on neural regeneration in models of spinal cord injury and glaucoma. The Horner Lab approaches the problem of regeneration by studying the biology of adult stem cells which reside in the human brain and spinal cord. In 2000, the Horner lab was the first to demonstrate that adult stem cells routinely replace supportive glia in the spinal cord throughout life. The discovery of adult stem cells has led to an exciting new perspective on brain plasticity and offers hope that activating or transplanting stem cells is a viable concept to replace or repair lost circuitry in the mature nervous system. The Horner Lab has isolated adult stem cells from adult rodent and human brain and genetically marked these cells for observing them in the setting of neural injury or degenerative disease. The Horner lab has shown that components of the blood can negatively impact the ability of the adult stem cell to repair the spinal cord. Blocking blood proteins may be a viable approach to promoting recovery from spinal cord injury. Another key method to stimulating nerve cell replacement will entail turning on genes in adult stem cells that are normally found in the developing spinal cord. This approach is being spearheaded through collaboration with the Moon lab.

Suman Jayadev (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.

Sean Murphy (Neurosurgery)
Our research is directed at finding interventions to improve outcome following acute brain injury.

Bensheng Qiu (Radiology)
Dr. Qiu is focusing on developing various molecular MRI techniques for stem cell-gene therapy, such as molecular MRI of neural stem cell-based gene therapy for brain tumors, MRI of vascular gene therapy and interventional MRI, and translating these new techniques to clinical applications.

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 and 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.

Robert Rostomily, MD (Neurological Surgery)
This lab’s long-term goal is to leverage connections between developmental neural stem and progenitor cell biology and human brain cancers to develop new strategies for treatment that can be rapidly applied in the clinical setting. The prognosis for the most common brain cancer, glioblastoma, has not significantly improved over the last 25 years and reflects a lack of understanding of the molecular, cellular and micro-environmental determinants of glial tumor cell phenotype. This is compounded by the failure of existing pre-clinical models to predict the response of new therapies in humans. The treatment-limiting biological features of human gliomas recapitulate the behaviors of neural stem and progenitor cells, but in an unregulated fashion. This observation motivates their synthesis of neural stem and progenitor and human glioma biology in the following areas with potential for therapeutic translation

  1. characterizing the role of developmental transcription factors in integrating pro-invasive signals into an invasive, anti-apoptotic and treatment resistant cellular phenotype;
  2. identifying relevant neural stem and progenitor cells in human brain tissue as candidate glioma cells of origin, and generating reliable methods for their isolation, immortalization and application to studies of glioma initiation and progression;
  3. refinement of animal glioma models by incorporating the effects of aging for both target cells and hosts; iii) investigate the potential therapeutic impact of boosting endogenous stem cell responses to gliomas as well as their utility as vehicles for treatment delivery.

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.

Valera Vasioukhin (FHCRC)
Our laboratory studies the mechanisms and significance of cell polarity and cell adhesion in normal mammalian development and cancer.

Zhengui Xia (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.

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