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Assistant Professor of Pediatrics Assistant Professor of Human Genetics |
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| 3520 MSRB I SPC 5652 1150 W. Medical Center Drive Ann Arbor, MI 48109 |
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The focus of the research in my laboratory is to understand the developmental pathways that are required for formation of the caudal portion of the embryo and the mechanisms that lead to birth defects affecting caudal structures in humans.
There are 2 major projects currently ongoing in the laboratory:
1. Mechanisms leading to the caudal regression phenotype in adrenocortical dysplasia (acd) mice.
Caudal regression syndrome (CRS) is a birth defect of the caudal region that is characterized by premature truncation of the vertebral column along with urogenital tract malformations. The etiology of CRS is unknown, but it is clinically very heterogeneous and likely has multiple etiologies. My laboratory studies the adrenocortical dysplasia (acd) mouse as a model for caudal regression syndrome. acd is a recessively inherited mouse mutation that causes embryonic lethality on certain genetic strains. The acd mouse was initially described as a model for human congenital adrenal hypoplasia, as the predominant defects in adult mice include adrenal insufficiency and reduced survival. We previously characterized a striking embryologic phenotype in acd mice that consists of caudal truncation, vertebral defects, and limb anomalies, resembling CRS in humans. The gene that is mutated in acd mice encodes a telomere protein named TPP1, which is a component of the shelterin telomere complex. Shelterin functions as a cap that protects telomeres from being recognized and processed by the DNA repair machinery and regulates telomerase access to telomeres. Consistent with the known function of TPP1 as a critical component of shelterin, cells from acd mutant mice exhibit evidence of telomere dysfunction and genomic instability. The role of telomere dysfunction in causing birth defects is unexplored; thus, the acd mouse is a unique model to study the mechanisms that lead to CRS, and the causative mechanisms are likely to be similar in humans. We are also interested in collecting patients with CRS phenotypes to potentially identify genetic etiologies of this disorder.
We are interested in pursuing the following questions:
1) What is the mechanism by which the acd mutation causes the CRS phenotype?
2) Why is the phenotype in acd mutant embryos restricted to the caudal region?
3) What is the role of telomere dysfunction and/or genomic instability in causing birth defects?
4) Are the underlying mechanisms the same for CRS that is caused by other genetic or environmental etiologies?
2. Genetic and genomic analysis in patients with cloacal exstrophy (OEIS complex).
Another focus of my laboratory is the identification of new genes that are required for proper formation of the caudal region of the embryo. To accomplish this goal, we are collecting samples from human patients with cloacal exstrophy (also called OEIS complex—omphalocele, exstrophy of the bladder, imperforate anus, spinal defects), which is a sporadic condition that includes defects of the bladder, bowel, and genital region in humans. The cause of cloacal exstrophy is unknown, but it is thought to involve improper migration of specific groups of cells during formation of the bladder, bowel and genital structures in the embryo. We are currently performing both genetic and genomic analyses to identify causative genes for this condition.
University of Michigan, 1988, B.S. in Cellular and Molecular Biology
University of Michigan, 1996, Ph.D. in Cellular and Molecular Biology
University of Michigan, 1996, M.D.
Member of University of Michigan MSTP program 1988-1996
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