CLONING OF A LEIOMYOMA ASSOCIATED GENE ON CHROMOSOME 14

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DESCRIPTION (Applicant's Description): Uterine leiomyomata (UL) are one of the most common human neoplasms, a major public health problem for women of reproductive age, and the most frequent indication for hysterectomy. The objective of this proposal is to isolate and characterize a gene involved in the pathobiology of UL. The proposed studies focus on a region (chromosome 14q23-24) consistently rearranged in about 10 percent of all UL. To positionally clone this leiomyoma-associated gene, Dr. Quade has constructed a cosmid library from a leiomyoma cell line containing the t(12;14) translocation and isolated cosmids containing this rearranged region. Under the sponsorship of Dr. Cynthia Morton, he will identify the gene by exon trapping and sample sequencing, isolate its cDNA, and characterize its expression and localization in UL and related tumors. Dr. Quade is a well-trained diagnostic surgical pathologist with clinical expertise in gynecological and obstetrical pathology. His primary interest is the pathobiology of smooth muscle tumors of the female reproductive tract. Although he has previous research experience, his postdoctoral training in molecular genetics and cytogenetics was a major departure from his predoctoral training in the cell biology and protein biochemistry of the extracellular matrix. Additional mentored training will allow him to build on the molecular biology skills he has acquired and provide a critical mass of experience necessary to make the transition to independent investigation in a highly competitive environment. Support provided by this award would be comparable to the final years of a full term K08 award. His ultimate goal is to establish an independent academic research career investigating the molecular pathobiology of uterine smooth muscle tumors and to apply that knowledge to improving histologic diagnosis and clinical treatment of these tumors. Dr. Morton's laboratory was among the first to clone a leiomyoma-associated gene (HMGI-C) by positional methods and is unique in its commitment to understanding the molecular genetics of uterine leiomyomata. The research environment within the Pathology Department and throughout the Harvard Medical School community is of the highest caliber and will provide Dr. Quade ample opportunities to interact with experienced molecular geneticists as he completes his training.