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Home > Neurosurgery Research > BTRC > Alvarez-Buylla Laboratory  
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Alvarez-Buylla Laboratory
Principal Investigator: Arturo Alvarez-Buylla PhD

Current Research Projects

 
Neural Stem Cells in the Adult Brain: Link to Tumors
Principal Investigator: Arturo Alvarez-Buylla
 
We are interested in the function and regulation of neural stem cells in the adult brain. We address questions about the mechanisms of neuronal birth, migration, and differentiation, and about how new nerve cells are integrated into and contribute to the function of postnatal brain circuits. The subventricular zone (SVZ), a very extensive germinal layer in the adult mammalian brain, contains large numbers of neural stem cells that can generate new neurons and glial cells throughout life. By means of chain migration, a novel form of neuronal translocation identified in our laboratory, young neurons born in the SVZ reach the olfactory bulb, where they become fully integrated into functional circuits. We have identified the neural stem cells in the SVZ. Surprisingly, the stem cells correspond to astrocytes. More recently we found that adult neural stem cells are heterogeneous and that particular types of neurons are derived from progenitors within specific locations of the SVZ. We are investigating the properties and ontogeny of astrocytes that function as stem cells in the rodent and human brain and the regulation of their proliferation. We are also interested in the mechanism of cell migration in the adult brain; how can cells migrate and orient during journeys through the very complex terrain of the adult brain? Once young neurons reach their destination, they need to integrate into neural circuits that are already functional. How is this accomplished? How do these new neurons contribute to plasticity without disturbing circuits that are active? These are some of the questions that keep us on the go. Three lines of research in the laboratory are tightly related to human disease:
 
Are Adult Brain Progenitors a Source of Brain Tumors?
Primary tumors of the central nervous system occur with high incidence in humans and remain clinically intractable. Since the 1940s, it has been suspected that the adult mammalian SVZ may be a source of astrocytomas. We are studying whether the stem cells or transit amplifying cells we have identified in the SVZ give rise to adult brain tumors. We have recently shown that adult SVZ neural stem cells express the receptor for PDGF. Under normal conditions, this receptor regulates the balance between generation of oligodendrocytes and neurons. However, over-stimulation through this receptor results in the formation of glioma-like masses next to the SVZ. We are studying how signaling through PDGF and other growth factor receptors is normally regulated and how deregulation could result in aberrant growth and possible initiation of tumor formation.
 
A Germinal Layer in the Adult Human Brain
The SVZ has been fully characterized only in rodents, macrosmatic animals with relatively large olfactory bulbs. Preliminary reports suggest an analogous structure exists in primates. It has been proposed that the SVZ may be an important source of neural stem cells for future therapies to treat neurodegenerative diseases, but its role in humans remains largely unknown. The clinical implications of stem cells in the postnatal brain range beyond that of their regenerative potential. We are conducting a detailed analysis of the adult human SVZ that will: (1) locate and define its organization; (2) characterize its cytoarchitecture and ultrastructure; (3) identify the target(s), mechanism(s), and extent of human neuroblast migration; (4) isolate the population of SVZ stem cells; and (5) determine the development of this germinal layer through late fetal, neonatal, and postnatal stages.
 
Neural replacement in the Cortex and Striatum

The above studies of the SVZ have demonstrated that migration and integration of new neurons can take place in juvenile and adult mammalian brain. This suggests new strategies for brain repair. However, under normal conditions, postnatal SVZ neuronal precursors migrate and integrate only in the olfactory bulb. This is a limitation for the use of these precursors for brain repair. In collaboration with other laboratories at UCSF we study populations of GABAergic inhibitory interneuron progenitors that can migrate and integrate into adult neural circuits outside the olfactory bulb. We have identified precursors in the ventral forebrain of the developing embryo that migrate long distances and fully develop into inhibitory local circuit neurons in the postnatal and adult brain. These cells disseminate and integrate particularly well in postnatal cortex where they increase local inhibition. These cells could be useful in the treatment of epilepsy and Parkinson's disease. Ongoing studies are using animal models for these diseases to determine the effects of increasing local inhibition.
 
 
UCSF UCSF Medical Center UCSF School of Medicine
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