Work in the Holz lab focuses on the crosstalk between estrogen signaling and mTOR (mechanistic target of rapamycin), two fundamental pathways that regulate growth and proliferation in the cell. One of the major unanswered questions is how cytoplasmic signaling by estrogen activates mTOR, and what downstream mTOR effectors are the specific targets of estrogen. This question represents a major gap in our understanding of the relationship between estrogen and mTOR signaling, with relevance to normal cell homeostasis and inappropriate signaling in many estrogen-dependent diseases. Two related projects stem from our published and preliminary data. First, we will examine how mTOR is activated by estrogen, and what downstream cellular events are initiated. To accomplish this goal, we will use quantitative proteomics and phosphoproteomics for signaling pathway discovery, followed by biochemical investigation and cell biology- based studies of estrogen- and mTOR-regulated proteins. Second, we will investigate the control of protein synthesis by estrogen. While regulation of transcription by estrogen is well studied, we propose to investigate an unexplored role for estrogen in mediating translational control. We will employ polysome profiling coupled with RNA-seq to identify translationally regulated estrogenic targets. The proposed research program will combine our interests in estrogen signaling and mTOR-regulated translational control, will allow us to freely generate new data and to explore exciting directions.

Public Health Relevance

Our proposal focuses on investigating the molecular mechanism by which Estrogen Receptor cooperates with the mechanistic target of rapamycin (mTOR) signaling in regulating cellular processes in homeostasis and disease. Specifically, we would determine how estrogen activates mTOR, and what downstream processes are subsequently affected.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM128675-02
Application #
9769074
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Koduri, Sailaja
Project Start
2018-09-01
Project End
2023-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595