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Tryptophan metabolism and its role in fibroid pathogenesis

色氨酸代谢及其在肌瘤发病机制中的作用

基本信息

批准号：
10504393
负责人：
OMID A. KHORRAM
金额：
$ 38.53万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504393
关键词：
African American population Aryl Hydrocarbon Receptor Binding CYP1B1 gene Catabolism Caucasians Cell Cycle Proteins Cell Proliferation Collagen Data Development Diet Dietary Factors Endocrine Disruptors Environmental Risk Factor Enzymes Epigenetic Process Exposure to Extracellular Matrix Fibroid Tumor Gene Expression Genes Goals Gonadal Steroid Hormones Growth Hispanic Populations Hormonal Hydrocortisone In Vitro Inflammation Kynurenine Leiomyoma Lentivirus Link Messenger RNA Metabolic Metabolic Pathway Mutation NF-kappa B Pathogenesis Pharmacology Quantitative Reverse Transcriptase PCR Race Reaction Receptor Signaling Reporting Response Elements Risk Factors Role Sampling Smooth Muscle Myocytes Specimen Stress Testing Tetrachlorodibenzodioxin Tissues Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan Metabolism Pathway Tryptophanase Untranslated RNA Ursidae Family Western Blotting Xenobiotics aryl hydrocarbon receptor ligand base cell growth design enzyme activity in vivo inhibitor innovation knock-down mRNA Expression mouse model myometrium novel novel therapeutics overexpression protein expression small hairpin RNA transcription factor transforming growth factor beta3 translational potential trend tumor

项目摘要

Abstract In the course of our profiling for non-coding RNAs in fibroids we discovered highly aberrant overexpression of Tryptophan 2,3 dioxygenase (TDO2) and Indoleamine 2,3-dioxygenase (IDO1) in fibroids. We confirmed this finding by both qRT-PCR and Western blot analysis, and found a consistently elevated expression of TDO2 and more variable overexpression of IDO1 in our tissue specimens. The increment in TDO2 expression in fibroids was higher as compared to IDO1, and the expression of IDO2 was barely detected. Relevant to the pathogenesis of fibroids was that the increment in TDO2 but not IDO1 was race dependent, with the increment being significantly higher in African Americans as compared with Caucasians. Furthermore, the expression of TDO2 was significantly increased in MED12 mutation bearing leiomyomas, and its inhibition by pharmacologic blockade in vitro led to decreased proliferation and expression of genes related to extracellular matrix, inflammation and cell growth in leiomyoma smooth muscle cells (LSMC) spheroids. Aberrant expression of these enzymes in fibroids resulted in increased levels of kynurenine (Kyn), a metabolic byproduct of tryptophan degradation and a known endogenous ligand for Aryl hydrocarbon receptor (AhR). Based on this preliminary data we hypothesized that dysregulation of Trp metabolism as characterized by marked overexpression of TDO2 is fundamental to the pathogenesis of fibroids and correction of Trp metabolic dysregulation by inhibition of TDO2 and normalization of kynurenine levels will inhibit fibroid growth and progression and potentially tumor establishment. We propose to this hypothesis in 3 aims. In aim1 we will characterize Trp metabolism in myometrium and fibroid tumors and explants, and determine the mechanism(s) underlying the marked overexpression of TDO2 in fibroids using an in vitro approach. In Aim 2 we will examine the impact of kynurenine and its activation of AhR on downstream genes regulating extracellular matrix (ECM), inflammation and cell proliferation. Aim 3 is designed to determine the utility of a pharmacological inhibitor of TDO2 and with lentivirus bearing shRNA to knock down TDO2 on fibroid establishment and progression in in vivo mouse models of fibroids. This novel metabolic mechanism for fibroid pathogenesis has great translational significance as it opens the way for novel therapies aimed at correction of tryptophan metabolism in fibroids.

摘要