Mitochondrial dysfunction and changes in cellular metabolism trigger several clinical conditions including cancer. It is critically important to understand the molecular mechanisms underlying the control of mitochondrial biogenesis and function, and metabolism in general, during normal development and oncogenic transformation. The remarkable conservation in molecular strategy controlling basic cellular processes allows the exploitation of powerful genetic tools developed in the Drosophila eye to study the control of mitochondria and metabolism. The proposed work intends to determine the mechanism by which developmental pathways in the eye primordium regulate mitochondrial structure and function. Also proposed is a study to better understand the mechanism by which a metabolic shift from oxidative phosphorylation to glycolysis takes place when an oncogene is activated. The proposal has three specific aims.
In AIM 1, the mechanism of control of mitochondria by Lozenge and its mammalian homolog, the oncogene Runx-1 (Acute myeloid leukemia-1/AML-1) will be explored in the context of the growth promoting Yorkie/Scalloped pathway and the steroid hormone receptor, EcR (Ecdysone receptor).
In AIM 2, the role of mitochondrial Complex I and two metabolic enzymes that also function as oncogenes, Sdh and Idh, will be studied in the context of oxidative stress response.
In AIM 3, the oncogenic influence on cellular metabolism and the molecular mechanism that causes a metabolic shift towards glycolysis will be investigated.

Public Health Relevance

Errors in cellular metabolism and mitochondrial dysfunction result in various metabolic diseases and disorders including cancer;it is important to understand the molecular mechanisms that regulate metabolism in order to develop appropriate treatment. Drosophila offers powerful genetic tools to dissect signaling pathways that control these metabolic processes. This proposal seeks to understand how developmental signaling pathways control mitochondria, the major organelles involved in cellular metabolism, and the relevance of changes in cellular metabolism to oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY008152-23
Application #
8295841
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1990-01-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
23
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$135,000
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Yan, Huajun; Canon, Jude; Banerjee, Utpal (2003) A transcriptional chain linking eye specification to terminal determination of cone cells in the Drosophila eye. Dev Biol 263:323-9

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