Ramin Homayouni, Ph.D.
Department of Biology
University of Memphis
Adjunct Associate Professor
Department of Neurology
Adjunct Assistant Professor
Department of Anatomy and Neurobiology
University of Memphis
Department of Biology
429 Smith Hall
Memphis, TN 38152
Phone: (901) 678-1670
Fax: (901) 678-4457
Lab: 503 & 505 Life Sciences Building
Email: Ramin Homayouni
My research interests are in three broad areas: 1) Mechanisms underlying neurodegeneration and Alzheimer’s Disease; 2) Mechanisms of mammalian brain development; 3) Genomics and Bioinformatics. Current research projects in my lab are summarized below.
Role of Amyloid Precursor Protein during normal development and in neurodegeneration associated with Alzhiemer’s Disease
Amyloid precursor protein (APP) is a transmembrane glycoprotein that plays a critical role in the pathogenesis of Alzheimer’s Disease. Presently, the physiological role of APP and its family members, amyloid precursor like protein 1 and 2 (APLP1 and APLP2), are unclear. Recent genetic studies in mice indicate that APP family proteins have essential and partially overlapping roles during development. APP family proteins have several structural features that are highly conserved. In addition, all three proteins are similarly processed by specific proteases in intracellular compartments. The proteolytic processing of APP is remarkably similar to that of Notch1, a transmembrane protein that is important in early development. Binding of extracellular ligands to Notch1 stimulates proteolysis and release of its intracellular domain which translocates into the nucleus and regulates gene expression. Recent studies indicate that the cytoplasmic domain of APP is released, enters the nucleus, and together with Fe65 adapter protein activates transcription, suggesting that APP is involved in a Notch-like signaling pathway during development. My laboratory is testing the hypothesis that APP family proteins function in a notch-like signaling pathway during brain development. We use a variety of molecular, cellular and genomic approaches to identify components in APP signal transduction pathway using genetically modified mice that lack a combination of APP family genes. One approach in the lab focuses on identification of ligands that bind to the extracellular domain of APP family proteins and modulate their internalization and processing. Another approach focuses on investigation of the role of APP family proteins in regulation of gene expression using DNA microarrays. Understanding the physiological function of APP family proteins may shed light into the molecular mechanisms underlying pathogenesis of Alzheimer’s Disease.
Role of Dab2IP, a novel GTPase activating protein, in the Reelin signaling pathway during brain development
The mammalian brain is formed through a series of intricately orchestrated events whereby neurons born in germinal zones migrate great distances to reach their final positions and form specific connections. Abnormalities in neuronal migration and positioning are believed to be responsible in part for disorders such as lissencephaly, pediatric epilepsy, schizophrenia and autism.
Recent genetic studies in mice have identified a key signaling pathway that controls cell positioning and formation of laminated structures throughout the mammalian brain. Mice with disruptions in reelin, disabled-1 (Dab1), or both very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) genes exhibit nearly identical histopathological abnormalities. Reelin is an extracellular protein that directly binds to the lipoprotein receptors and induces tyrosine phosphorylation of Dab1. Dab1 is an intracellular adapter protein that is required for Reelin signaling. The long-range goal of this project is to identify molecular components downstream of Dab1 in the Reelin signaling pathway and to understand the mechanism by which Reelin controls neuronal positioning. Using a yeast two-hybrid strategy, we found that Dab1 interacts with amyloid precursor family proteins, protocadherin-18 and a novel protein similar to GTPase activating proteins, termed Dab2IP. The deduced amino acid sequence of Dab2IP encodes a Ras GAP related domain and several protein-protein interaction domains, including an NPxY PTB-interacting motif. We hypothesize that Dab2IP functions as a regulator of GTPases and, by virtue of its interaction with Dab1 and other intracellular proteins, is the downstream effector in the Reelin signaling pathway. Future aims in this project include: 1) Characterization of the activity, regulation and cellular function of Dab2IP; 2) investigation of the effect of Dab1 on Dab2IP activity; 3) investigation of the physiological role of Dab2IP by targeted disruption in mouse. Understanding the biological function of Dab2IP and its role in Reelin signaling will provide valuable insight into the molecular mechanisms of neuronal migration and cell positioning during brain development.
Gene clustering using Latent Semantic Indexing of MEDLINE abstracts
Recent advances in genomics and DNA microarray technology enable investigators to simultaneously analyze the expression of thousands of genes under different experimental conditions. However understanding the functional relationships between co-regulated genes presents a formidable task to investigators, requiring first hand knowledge of the biological characteristics of each gene.
There are a variety of public electronic resources from which investigators may assemble gene information. For instance, there are over 10,000 annotated human genes in LocusLink and nearly 13 million citations archived in MEDLINE. However, better automated tools are needed to aid in extraction and utilization of gene information from these databases. My lab has been collaborating with Dr. Michael Berry (Professor of Computer Science at The University of Tennessee, Knoxville; http://www.cs.utk.edu/~berry/) to develop a new software environment called Semantic Gene Organizer©(SGO) (http://shad.cs.utk.edu/sgo/sgo.html ) to automatically extract gene relationships from titles and abstracts in MEDLINE citations. SGO utilizes a variant of the vector-space model of information retrieval called Latent Semantic Indexing (LSI). LSI implements a classical factorization method from linear algebra (singular value decomposition) to identify conceptual relationships between documents. Our studies have provided proof-of-principle that LSI is a robust automated method for identification of gene-to-keyword and gene-to-gene relationships from the biological literature. Future aims of this project include: 1) expansion of the gene-document collection to include all genes in the LocusLink database; 2) Utilize SGO to expand gene ontology terms and functional gene annotation.
- McKimm E, Corkill B, Goldowitz D, Albritton LM, Homayouni R, Blaha CD, Mittleman G. Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders. Cerebellum. 2013 Dec 5. [Epub ahead of print] PubMed PMID: 24307139.
- Cashion A, Stanfill A, Thomas F, Xu L, Sutter T, Eason J, Ensell M, Homayouni R. Expression levels of obesity-related genes are associated with weight change in kidney transplant recipients. PLoS One. 2013;8(3):e59962. doi: 10.1371/journal.pone.0059962. Epub 2013 Mar 27. PubMed PMID: 23544116; PubMed Central PMCID: PMC3609773.
- Qiao S, Kim SH, Heck D, Goldowitz D, LeDoux MS, Homayouni R. Dab2IP GTPase activating protein regulates dendrite development and synapse number in cerebellum. PLoS One. 2013;8(1):e53635. doi: 10.1371/journal.pone.0053635. Epub 2013 Jan 9. PubMed PMID: 23326475; PubMed Central PMCID: PMC3541190.
- Xu L, Cheng C, George EO, Homayouni R. Literature aided determination of data quality and statistical significance threshold for gene expression studies. BMC Genomics. 2012;13 Suppl 8:S23. doi: 10.1186/1471-2164-13-S8-S23. Epub 2012 Dec 17. PubMed PMID: 23282414; PubMed Central PMCID: PMC3535704.
- Lee GH, Kim SH, Homayouni R, D'Arcangelo G. Dab2ip regulates neuronal migration and neurite outgrowth in the developing neocortex. PLoS One. 2012;7(10):e46592. doi: 10.1371/journal.pone.0046592. Epub 2012 Oct 4. PubMed PMID: 23056358; PubMed Central PMCID: PMC3464295.
- Swanson JM, Wood GC, Xu L, Tang LE, Meibohm B, Homayouni R, Croce MA, Fabian TC. Developing a gene expression model for predicting ventilator-associated pneumonia in trauma patients: a pilot study. PLoS One. 2012;7(8):e42065. doi: 10.1371/journal.pone.0042065. Epub 2012 Aug 15. PubMed PMID: 22916119; PubMed Central PMCID: PMC3419717.