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Michael Dean, Ph.D.
Genetic Analysis of Complex Diseases
Our laboratory's objective is to develop methods for analyzing complex diseases and to apply them to human genetic conditions, cancer, HIV infection, and disease.
Resistance of tumors to several drugs (multidrug resistance, or MDR) is a major limitation of cancer chemotherapy. In some tumors, MDR is due to the overexpression of the P-glycoprotein (PGP)/MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of the ATP-binding cassette (ABC) family of transporters. We have characterized the complete set of human ABC genes, bringing the total of human ABC genes to 48. [See http://theta.ncifcrf.gov/abc_central/index.php for links to all sequences]
One of these genes ABCG2/MXR is a multidrug transporter important for resistance to mitoxantrone and other drugs. The gene is also expressed in early stem cells and may protect these cells from damage.
Several ABC genes are invlolved in human genetic disease. ABCA4/ABCR, is expressed exclusively in the retina, in rod photoreceptor cells. The gene is responsible for the recessive retinal degeneration syndrome Stargardt disease, and is also mutated in some patients with retinitis pigmentosa and cone-rod dystrophy. Some parents of Stargardt disease patients have age-related macular degeneration (AMD). AMD is the most common cause of vision loss in the elderly, and we have found that a significant portion of AMD patients have mutations in one allele of the ABCA4/ABCR gene, suggesting that this gene can predispose individuals to AMD. The ABCG5 and ABCG8 genes are expressed in the intetine and liver and are mutated in patients with the recessive disease sitosterolemia. These patients have defective reteintion of non-cholesterol sterols and resultant xanthomas, arthritis and hypercholesterolemia. The ABCA3 gene is expressed in type II alveolar cells in the lung and is mutated in many neonates with deficiency in lung surfactants. This is a fatal disorder resulting in respiratory distress at birth. Milder mutations in this gene may give rise to later onset pulmonary diseases.
Although some cancers are inherited as a genetic disorder, the vast majority of cancers occur from a complex combination of genetic and environmental factors. To understand the role of estrogens in breast cancer we have characterized variation in the estrogen and progesterone receptor genes. These studies indicate that estrogen receptor variation plays a role in breast cancer.
Inflammation is thought to be an important factor in the development of cancer. One of the body's important defense mechanisms against bacteria and fungi are the complement proteins. By studying variants in one of the complement genes, complement factor H (CFH) we have identified this gene as critical to the development of age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly and is estimated to effect as many as of 10 million Americans. AMD is a complex disease, with onset typically after the age of 65, and the known risk factors include smoking, diet, and age. Women are more often affected by this disease, and it is the leading cause of vision loss in the elderly. There is also strong evidence for a genetic contribution to the disease. We previously identified a role of the ABCA4 gene in AMD, but the contribution of this gene is small. Through the analysis of a rare kidney disease caused by mutations in the CFH gene, it was demonstrated that these people also have an early onset form of AMD. By examining the eight genetic variants in the CFH gene, we found a significant association between these variants and the disease. The most common at-risk genotype was found in 50% of AMD patients and only 29% of controls. We also found an accumulation of the CFH protein in ocular drusen, characteristic deposits associated with the early stages of AMD. The research is a major breakthrough in the understanding of AMD. It suggests an infectious agent might be a critical trigger, and that by identifying the pathogen the disease may be prevented or its progression limited. The complement pathway may also be important in the bodies response to other pathogens and irritants associated with cancer. Further study of this important component of innate immunity could lead to insight into human disease.
Cancer Stem Cells
The identification of a small population of self-renewing cells in many solid tumors (Cancer stem cells) has opened up new approaches to cancer therapy. We previously cloned the PTCH gene as a tumor suppressor. PTCH is the receptor for Hedgehog (HH) proteins and this pathway is critical to normal stem cell development. HHs are overexpressed in many tumor types including pancreas, prostate, GI and small cell lung tumors.
We have developed new peptide reagents against the SMO protein, a critical signaling molecule for PTCH. These peptides block the growth of several cell lines with HH activation and downregulate HH/PTCH gene and protein expression.
The ABCG2 protein is also highly expressed in cancer stem cells and we have completed a screen for new drugs that inhibit this transporter.
Collaborators on our research are Z.Q. Chen, and Julie Sawitzke, SAIC-Frederick; Larry Nogee Johns Hopkins Medical School:, Sam Broder, Celera and Ken Offitt, Memorial Sloan-Ketting; Rando Allikmets, Columbia University; and Greg Hageman, University of Iowa.
This page was last updated on 7/10/2013.