Leiomyomas are highly pervasive benign tumors of the uterus that have an overall prevalence of 70% in women by the age of 50. They are the leading cause of hysterectomy in the United States, accounting for almost 50% of the 600,000 hysterectomies performed annually and $34 billion dollars in annual healthcare costs. Despite their prevalence and public health impact, the cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Phenotypically, these tumors are distinct from the adjacent normal tissue largely due to the overproduction of extracellular matrix component, especially the major fibrillar collagens (I, II, and III). We, and others, have demonstrated that in addition to differentially expressed genes between LEIO and MYO, there is differential expression of microRNAs, suggesting that they play a role in gene regulation of these tumors. MicroRNAs are a class of small non-coding RNAs that negatively regulate gene expression. While several studies have documented hormonal and growth factor regulation of miRNAs in leiomyomata, none have demonstrated a functional role for them in terms of their main distinguishing pathological finding: excessive collagen deposition. Our lab has found that all of the members of the miR-29 family (29a, 29b, 29c) are downregulated in leiomyoma versus normal myometrial tissue. Based on recent studies in other fibrotic diseases and preliminary data included in this application, we hypothesize that this dysregulation of the miRNA-29 family plays a functional role in the aberrant extracellular matrix components found in leiomyomata. To address this hypothesis, we propose the following two specific aims:
In Specific Aim 1 we seek to determine the mechanism by which TGF-?3 regulates miR-29 levels in uterine leiomyomas. TGF-?3 is known to be present in higher concentrations in leiomyoma versus adjacent normal myometrial tissue. To determine its role in the regulation of miRNA-29, we will perform SMAD2/3 knockdown and chromatin immunoprecipitation studies.
In Specific Aim 2, we will determine the contribution of the miR-29 family (a/b/c) to the excess major fibrillar collagen production in uterine leiomyoma. The role of miRNA-29 will be assessed using knockdown and overexpression studies. The results from these studies will not only provide mechanistic information on the excess extracellular matrix seen in leiomyomas, but will also lay the foundation for future preclinical studies as our understanding of both miRNAs in human disease and oligonucleotide based therapeutics continues to expand.
Uterine leiomyomas are benign uterine tumors that effect up to 70% of women by the age of fifty. They are the leading cause of hysterectomy in the United States and account for more than $34 billion dollars in health care costs annually. Our proposal to study the role of the miRNA-29 family in leiomyomas will improve our knowledge of the growth mechanisms for these tumors and will facilitate the implementation of novel medical treatments.
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