Characterization of Estrogen-mTORC1 Signaling Network in TSC/LAM
Abstract
The proposed work centers on the following Focus Area: Eradicating tumors associated with TSC and TSC-associated lymphangioleiomyomatosis (LAM), including gaining a deeper mechanistic understanding of TSC signaling pathways. In the Holz lab, we have a long-standing interest in understanding how the hormone estrogen contributes to LAM, and the relationship between estrogen, mTOR, and TSC deficiency. We are proposing to investigate molecular and biochemical questions studying this relationship, and we will obtain new information about how estrogen activates mTOR in cells, and the gene expression program that is regulated by estrogen and mTOR in the nucleus. While our investigation is mostly mechanistic, the answers will allow us to understand the action of estrogen in LAM and identify new ways in which we can develop treatment strategies for this disease. We have previous experience studying these questions in breast cancer, where we uncovered some new ways in which mTOR is regulated in response to estrogen, by not only affecting mTOR activation, but also transcription and protein synthesis of some of the components of its network. Like hormone-positive breast cancer, LAM is also driven by estrogen, and TSC deficiency in LAM cells creates an opportunity to not only understand how mTOR is activated by estrogen in the absence of TSC, but also to identify what signaling pathways and effectors are controlled by estrogen. We will use cutting-edge global mass spectrometry and chromatin immunoprecipitation strategies to create a snapshot of the entire cellular pathway activity and gene expression programs. We expect to uncover actionable targets that could be targeted with the existing FDA-approved agents. In addition, we will be able to characterize new actionable targets for future drug development. Overall, this project will create a wealth of information that will allow us and other groups to implement additional preclinical and clinical studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110467
Entities
People
- Marina K Holz
Organizations
- New York Medical College
- United States Army