Chief Executive Officer
The Parkinson's Institute and Clinical Center
675 Almanor Avenue
Sunnyvale, CA 94085
1999 Searle Scholar
Molecular Analysis of Human Neurological Disorders
The goal of the research in my laboratory is to understand disorders involving the brain.
Virtually all diseases have a genetic component. Our efforts are designed to use molecular biology, genetics and neurobiology to elucidate molecular mechanisms of human neurologic disease.
Mouse models serve as a basis to study the fundamental mechanisms of inherited and acquired genetic disorders of the central nervous system. We use standard transgenic techniques and homologous recombination to create mice with genetic alterations similar to those found in human neurologic diseases. In addition to this genetic strategy, we have used the binary Cre-loxP system to generate transgenic lines with tissue specific inactivation of genes. Such strategies are being applied to study molecular pathways in the nervous system. These mutants provide the basis for a genetic and molecular dissection of defective pathways leading to neurologic dysfunction.
In addition to standard molecular biological and neurobiological techniques, we also use the emerging technology of RNA expression arrays to identify differences in gene expression between normal and abnormal mice. This will allow us to identify both novel and known genes involved in brain disorders.
We have used this experimental approach to analyze the function of the gene Atm, mutated in the human disease Ataxia-Telangiectasia (A-T). A-T is a lethal, progressive human disorder with the hallmark clinical manifestations of progressive neurological degeneration. This line of Atm deficient mice provides an excellent model for understanding the role of ATM in normal cellular function as well as pathophysiology, and for testing potential therapeutic agents to treat the progressive, debilitating manifestations of A-T. One of the experimental approaches we employ to understand the role of ATM in the brain is to use microdissected brain regions from these mice for RNA expression analysis in order to identify novel and known genes whose expression is abnormal in the absence of ATM. By analyzing the expression pattern of RNA fragments in the tissues from the Atm-deficient mice in comparison to tissues from normal mouse, we hope to identify targets, either direct or indirect, of ATM which may help to explain the neuronal dysfunction.
We are also taking advantage of the rapid increase in genetic sequence available in the public domain. Using database searching, we identify new genes which we believe play a role in human brain disorders. We have identified several genes which are mammalian homologues of known drosophila genes which when mutated in drosophila give rise to specific neurodegenerative phenotypes. We are currently mapping the genes in human and mouse and using homologous recombination to delete these genes in mice.
This approach allows us to identify novel genes and previously cloned genes whose protein products are important for normal brain function. Our efforts are designed to use a multidisciplinary approach to contribute to the understanding of the molecular basis of human neurologic disease.
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