With the expansion in technologies and the required expertise to implement them, it has become necessary for principal investigators to rely on scientists with a more permeant scientific position in order to maintain scientific output and continuity. To promote the development of these research specialists, the NCI recently established a new funding mechanism, the R50, to pay the salary of career scientists who do not want to become independent investigators, but rather want to pursue research within an existing NCI funded program. As a research specialist, I will actively participate in two separate but related research programs in the Tansey laboratory, both of which stem from my recent work that defined a function for the central portion of MYC. The MYC oncogenes encode a family of related transcription factors that are overexpressed in the majority of cancers and contribute to an estimated 100,000 cancer-related deaths in the USA every year. MYC proteins derive their oncogenicity from their ability to bind chromatin and to modulate the transcription of thousands of genes controlling cell growth, cell cycle progression, angiogenesis, metastasis, genomic instability, and metabolic reprograming. While it has been demonstrate that certain epigenetic modifications are a prerequisite for MYC binding to chromatin, a long standing issue has been determining how exactly MYC is recruited to its target genes within the context of chromatin. Because several motifs within the central portion of MYC are highly conserved throughout evolution I reasoned they might be important for MYC function. To test this hypothesis, I designed a strategy that integrated two-hybrid and proteomic screening of the central portion of human c-MYC and identified WDR5 as a bonafide MYC interacting protein. WDR5 functions as a central component of several epigenetic `writer' complexes, including the MLL1 methyltransferase where its canonical role is to stimulate enzymatic activity by bridging MLL1 to its co-activators. I demonstrated that WDR5 is essential for targeting MYC to its target genes and that this interaction is necessary for MYC induced tumor formation and the genesis of induced pluripotent stem cells. Based on these seminal findings, we propose to test our model of Facilitated Recruitment, which posits that widespread association of MYC transcriptional complexes with target gene chromatin involves two critical sets of interactions: one with DNA and another with pre-bound and proximal WDR5 (to be funded by the NCI - 1R01CA200709). We also hypothesize, and in collaboration with the Fesik group at Vanderbilt, that we can identify small molecules that prevent WDR5 from engaging MLL1 as a means of cancer therapy (Funded by NCI Experimental Therapeutics Program Subcontract No. 29XS129TO27). The purpose of this grant is to cover my salary for these two research programs in the Tansey laboratory.

Public Health Relevance

My role as a Research Specialist in the Tansey laboratory lies at the crossroads of basic tumor mechanisms and targeted drug discovery and validation. Since joining the Tansey laboratory in 2010, I have initiated and sustained novel projects focused on MYC, which in turn have expanded into drug discovery efforts targeting MYC- and MLL1-fusion-driven malignancies via the epigenetic regulator WDR5. My tenure in the Tansey laboratory, together with a unique set of skills I have accrued over the last 15 years, provide the continuity, experience, and technical know-how required to move these critical projects forward.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
5R50CA211305-02
Application #
9567939
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Sharman, Anu
Project Start
2017-09-20
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
965717143
City
Nashville
State
TN
Country
United States
Zip Code
37240