Pedro Gonzalez-Alegre M.D. [Former faculty]

John R Manak Ph.D.

Current
John
R
Manak
Ph.D.
Associate Professor
Biology
Research area(s): 
Genetic basis of human disease using high-throughput genomics methodologies, fruit fly models of human disease and cancer.
Address
459A
BB
455=9A
BB
Research
Research Focus: 

Research in my laboratory covers three different but not mutually exclusive areas: 1) high-throughput genomics technologies to identify the genetic basis of human disease, 2) fruit fly models to understand human diseases such as epilepsy and cancer, with an emphasis on chromatin structure, 3) genomic technology development to facilitate identification of important mutations in both humans and model organisms. 

For the first project, we are utilizing array-based comparative genomic hybridization (aCGH) to identify copy number variants associated with a number of diseases, including cleft lip and palate, spina bifida, and renal agenesis (all relatively common birth defects).  Using this approach, we identify genes whose copy number is altered in affected individuals, and we functionally validate these disease-associated genes in vertebrate animal models such as frogs and fish.  Additionally, we are using exome sequencing to explore the genetic basis of the aforementioned diseases.  This new genomics technology allows enrichment and high-throughput sequencing of the protein-coding exons in the human genome; since roughly 85% of the mutations causing Mendelian disorders are thought to reside in such exons, this strategy eliminates the need for costly whole-genome sequencing.  However, this type of analysis requires careful selection of pedigrees that show strong Mendelian inheritance patterns of the disease, which is turn suggest that high effect loci are at play in the disease process in these families. 

For the second project, we are studying the Drosophila homolog of the c-Myb proto-oncogene (which causes leukemia and lymphoma in birds and mammals).  In particular, we are exploring the role of Drosophila Myb (Dm-Myb) in modulating chromatin structure and controlling gene expression.  Our recent results demonstrate that the Myb protein is controlling gene expression through its interaction with other chromatin-modulating factors, and that Myb is regulating different targets in different cell types.  Most interestingly, in contrast to the dogma in the field, Myb is a potent repressor of large numbers of genes in certain specialized cell types.

Additionally, we are using the Drosophila system to model another human disease, myoclonic epilepsy.  We have shown for the first time that the same gene mutated in flies, mice and humans causes this form of epilepsy, and that the epileptic flies can be successfully treated with human anti-epileptic medications (Am J Hum Genet, 2011).  Intriguingly, the mutated gene is prickle, a gene that has been shown to be involved in establishing planar cell polarity.  A number of laboratories have worked on this gene over the course of many years with regard to its involvement in planar polarity; however, up until now the epileptic behavioral phenotype had been missed.        

For the third project, we are developing a novel mutation mapping technology (in collaboration with my colleague in the dept, Josep Comeron) in order to efficiently and cost-effectively map both human disease-causing mutations as well as mutations of interest in a variety of model organisms, including mice and flies.  Currently, our technology can correctly identify known SNPs with an accuracy of 99% and we are now using the technology to identify novel mutations in several human diseases.    

Faculty affiliations: 

Curt D Sigmund Ph.D.

Professor
Pharmacology

Andy F Russo Ph.D.

Current
Andy
F
Russo
Ph.D.
Professor
Molecular Physiology & Biophysics
Research area(s): 
Eukaryotic Gene Expression; Molecular and Biochemical Genetics
Address
5-432
BSB
5-433
BSB
Research
Research Focus: 

My research interest is the control of neuronal gene expression. The major focus of the lab is on the neuropeptide CGRP and its role in migraine. The role of CGRP in migraine is supported by the ability of CGRP to cause headache and the recent efficacy of a CGRP antagonist as an antimigraine drug. We have found that the CGRP gene is up-regulated by cytokine-induced MAP kinases and repressed by antimigraine drugs that appear to act via an unusually prolonged calcium signal. We are currently investigating these mechanisms using adenoviral-mediated gene transfer to cultured trigeminal neurons and intact ganglia in vivo. We are also using gene transfer and transgenic mice to regulate CGRP receptor activity in the vasculature and nervous system by overexpressing the RAMP1 subunit of the CGRP receptor. The RAMP1 transgenic mice are sensitized to CGRP-induced neurogenic inflammation. The RAMP1 transgenic mice display a unique phenotype has raised the possibility that these mice may provide a model for some aspects of migraine, which is currently being explored. In collaborative projects, we are studying the beneficial effects of CGRP against hypertension and following myocardial infarction in the RAMP1 mice. Other collaborative projects include the regulation of serotonin biosynthesis, which may be important in migraine and behavioral disorders, and use of the CGRP promoter to target a dominant negative oncogene to specific neuroendocrine cells. The overall goal of these projects is to develop effective diagnostic and therapeutic strategies.

Toshihiro Kitamoto Ph.D.

Current
Toshihiro
Kitamoto
Ph.D.
Associate Professor
Anesthesia and Pharmacology
Research area(s): 
Nervous System and Genetic Variation
Address
1-316
BSB
1-376
BSB
Research
Research Focus: 

How does the nervous system control complex behavior? How do experience and genetic variation modify it? The goal of our research is to answer these fundamental questions in neuroscience. We use the fruitfly, Drosophila melanogaster as an experimental animal, and integrate knowledge of the nervous system at the molecular, cellular, systemic and whole animal levels. The current focus is on male courtship behavior. This behavior consists of a highly stereotypical sequence of activities that are genetically determined, but also shows considerable experience-dependent plasticity called \"courtship conditioning\". By examining the behavior of various genetic variants, we study the function of particular genes in different aspects of courtship. In addition, using a recently developed strategy that allows one to perturb synaptic transmission rapidly and reversibly in a spatially restricted manner in intact animals, we investigate the significance of particular neuronal subsets in sexual orientation, courtship initiation, and courtship memory. Our multidisciplinary research is expected to provide new insights into the basic mechanisms underlying higher-order brain functions that control complex behavior.

Faculty affiliations: 

Pedro Gonzalez-Alegre M.D.

Assistant Professor.
Neurology

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