My clinical and research training has long been geared towards a career as a physician-scientist who is able to bridge the gap between clinical observations and basic science approaches to these problems. This application is a critical part of my growth in this regard, and will ensure that I have the resources necessary to achieve this goal. PROJECT SUMMARY: Disorders of pigmented melanocytes are responsible for a number of human diseases, from the hypopigmentation of vitiligo to the fatal consequences of malignant melanoma. Understanding the genetic pathways that are involved in the development of the neural crest and its derivatives, including melanocytes, is a critical component of treating diseases of these lineages. In this proposal, I plan to use the zebrafish to understand how perturbations in the normal development of embryonic neural crest and melanocyte precursors is related to adult pigmentation disease such as nevi and melanoma. We have developed transgenic BRAF;p53 mutant fish that are morphologically normal as embryos yet have severe pigmentation disruption and melanoma as adults. Gene expression analyses demonstrates a conserved gene signature between BRAF;p53 embryos and tumors, suggesting a link between events early in embryogenesis and tumor formation.
In Specific Aim 1, 1 have utilized this information as the basis of a chemical screen to identify pathways and molecules that are relevant to preventing initiating events in melanoma formation. Hits which emerge from this screen are tested for their ability to alter the adult BRAF;p53 phenotype. Preliminary data of one hit, MLT013, demonstrates that it inhibits pigment stripe disruption as well as melanoma transplantability. MLT013 likely functions through endothelin receptor blockade.
In Aim 2, 1 describe experiments which determine whether endothelins cooperate with BRAF to drive melanoma formation. These studies aim to uncover novel signaling pathways that will provide the rationale for future studies as an independent investigator, and may offer therapeutic benefit to patients with nevi and melanoma. LAY SUMMARY: Our current understanding of diseases related to pigmentation, such as moles and melanoma, is limited. The zebrafish has yielded important insights into the biology of these diseases, and I plan to study this fish as a tool for identifying new pathways and drugs for the treatment of these human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR055368-04
Application #
8207200
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Tseng, Hung H
Project Start
2009-01-01
Project End
2012-04-30
Budget Start
2012-01-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$33,620
Indirect Cost
$2,490
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115