Stem cells have the ability to self-renew and differentiate into a variety of tissue types. They also play an important role in tumor relapse and progression in cancer. The molecular mechanism regulating stem cell function remains poorly understood. Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue malignancy in children with pathologic features of abnormal fetal muscle development. It is thought that the cancer stem cells contribute to treatment resistance and tumor relapse. We have previously identified the self-renewing tumor-initiating cell population in a zebrafish model of ERMS, which shows morphologic and molecular features resembling the human counterpart. We have also shown that the self-renewing ERMS cell is molecularly similar to an activated satellite cell in muscle. In skeletal muscle, satellite cells are a population of muscle progenitor cells that play an essential role in postnatal growth, repair and regeneration. Our central hypothesis is that there are common pathways that regulate stem cell function in muscle regeneration and progression of rhabdomyosarcoma. In this proposed study, we will identify FDA-approved drugs that act as positive and negative regulators of stem cell renewal in muscle regeneration and ERMS. We will then determine the common molecular pathways that alter stem cell function in muscle and characterize the mechanism by which each candidate pathway exerts its effect on muscle self- renewal. Our long-term goal is to better understand mechanisms underlying regulation of muscle stem cell function. The candidate for this career development award is an M.D./Ph.D. physician scientist with board certification in anatomic pathology. The research proposed in this grant application will be conducted under the mentorship of Dr. David Langenau. The candidate is committed to a career as a physician scientist and seeks further scientific training. This mentored clinical scientist development award will facilitate the candidate's transition to eventually become a competitive NIH-funded independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR063165-02
Application #
8546269
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2012-09-17
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$131,760
Indirect Cost
$9,760
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Chen, Eleanor Y; DeRan, Michael T; Ignatius, Myron S et al. (2014) Glycogen synthase kinase 3 inhibitors induce the canonical WNT/?-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:5349-54
Chen, Eleanor Y; Dobrinski, Kimberly P; Brown, Kim H et al. (2013) Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genet 9:e1003727