Tayebeh Pourmotabbed, Ph.D.
858 Madison Ave.
801 Molecular Science Building
Memphis, TN 38163
Our laboratory is interested in A. Cancer gene therapy, B. Determining the relationship between structure and function of matrix metalloproteinases (MMP), and C. Identifying risk factors in Alzheimers and coronary artery disease.
The matrix metalloproteinases secreted by connective tissue cells are considered to play a central role in both normal connective tissue remodeling and the accelerated matrix breakdown associated with tumor cell invasion and metastasis. Over the years, much information has accumulated which would implicate metalloproteinases in tumor cell invasion and metastasis. First, matrix metalloproteinases are fully active at physiological conditions and avidly degrade the major basement membrane components including type IV collagen and laminin, and activates several cytokines and chemokines. Second, these enzymes are increased in malignant tumors and are produced by the transformed cells and stroma cells. Third, the synthesis of these enzymes is upregulated by cytokines that are also present in increased amounts in tumor cells. Fourth, inhibitors of protein synthesis block the invasion of extracellular membrane by tumor cells apparently via inactivation of matrix metalloproteinases. Lastly, the inhibitors of the matrix metalloproteinases arrest the tumor cell invasion in vitro and prevent metastases in vivo.
Cancer Gene Therapy
The primary focus in my laboratory is to inhibit tumor growth and cell invasion by gene therapy. 1. Gene therapy of glioma targeting MMP: Glioblastoma multiforme is the most common and malignant of all the primary brain tumors. This brain cancer aggressively infiltrates surrounding normal tissue, resulting in distant foci throughout the central nervous system thereby rendering this tumor surgically incurable. The development of a therapeutic strategy that directly targets the microinvasion process would provide for an attractive adjuvant to surgery. Increased expression of matrix metalloproteinases (MMP) 2 and -9 have been shown to be associated with human glioblastoma tumor progression. We have designed and tested in vitro the ability of several mRNA cleaving deoxynucleotides (DNAzymes) that targets either the MMP-2 or MMP-9 transcript to decrease MMPs expression and inhibit tumor cell invasion. Using DNAzyme targeted to rat MMP-9 in an intracranial glioma model, we found that this therapeutic strategy could effectively and significantly reduce the overall tumor volume. Only one dose of anti rat MMP-9 DNAzyme delivered intracranially to the brain of rats bearing C6 glioma is sufficient to profoundly inhibit tumor growth and decrease the tumor size on average by 70%. These data demonstrate that anti-MMP DNAzyme can be effectively used as a therapeutic regimen in the treatment of metastatic cancer. The advantages of DNAzyme technology over the other anti-tumor therapies are specificity, ease of delivery, stability of the drug, and lack or low cytotoxicity. At the present, we are assessing the efficacy of DNAzyme on the rate of survival of animals bearing glioma. 2. Gene therapy of breast cancer targeting MMP: Since the DNAzyme treatment demonstrated a profound effect on glioma tumor volume we are expanding the DNAzyme therapy to the breast cancer.
Structure and function of metalloproteinases
The secondary objective is to unravel the mechanism of action of matrix metalloproteinases in order to be able to control their activity in vivo and subsequently design specific inhibitors for these enzymes to prevent tumor invasion. Towards the achievement of this goal we are studying the mechanism of activation and substrate specificity of these enzymes using site directed and deletion mutagenesis. In addition, we are interested in transcriptional regulation of matrix metalloproteinases in tumorogenic and metastatic cells.
Risk factors in Alzheimer and coronary artery disease
In collaboration with a group of scientist headed by Dr. Vaisi in the Department of Medical Biochemistry, Kermanshah University of Medical Sciences, Iran, we are assessing the association between apolipoprotein E (ApoE) polymorphism, Alzheimer, and coronary artery disease (CAD) in Iranian population.
- B.A., 1981, Chemistry, College of Notre Dame of Maryland
- Ph.D., 1986, Biochemistry, University of Maryland, Baltimore County
- Postdoctoral, 1986-88, Biochemistry/Molecular Biology, University of Maryland, College Park