Study Drosophila orthologs of human disease genes to understand their functions; study the intricacies of cancer metabolism in Drosophila.

Dr. Perrimon’s developmental and cancer biology studies, using RNAi in Drosophila, are yielding new insights into basic biological mechanisms in metazoans, including humans. His lab uses the powerful RNAi gene repression technology in Drosophila to gain important insights into functional aspects of Drosophila genes. The development of high throughput screens based on RNAi enhances the lab’s capability to decipher biological pathways. Drosophila studies offer distinct advantages over studies in mammalian cells; for example, the ability to generate results from genetic and developmental experiments in a relatively short timeframe. In addition, Drosophila is one of the best characterized model organisms, because so much genetic and phenotypic data is available. Because there are many corresponding human genes in Drosophila, these studies have the potential to illuminate the genetic basis of different human diseases.

Dr. Perrimon employs modern genetic screening methods to understand mechanisms of biological development, using Drosophila as a genetic model. His current projects include:

• Muscle physiology – Study cellular homeostatic pathways in muscle, including autophagy, insulin signaling, and mitochondrial biogenesis. In vivo and in vitro RNAi-based methods are important tools for these studies.

• Signaling pathways in cancer – Investigate the key signal transduction pathways that are deregulated in cancer cells. These pathways include the Wnt and JAK-STAT circuits. The lab is using its expertise in RNAi, Drosophila genetics, and microarray technology, to identify new components of these signaling networks and elucidate cross-talk among the different pathways.

• Drosophila RNAi Screening Center – Develop a high throughput resource for the scientific community. Screens are performed in-house, and can be applied to cultured cells, or in vivo with flies that have a single gene repressed by RNAi.

Dr. Perrimon studies developmental biology and biochemical signaling pathways in the Drosophila fruit fly. He has made noteworthy accomplishments in these areas, and his election as a Howard Hughes Medical Institute investigator attests to his scientific contributions. His recently published studies include a global analysis of signaling through c-Jun N-terminal kinases (JNKs), RNAi screens to explore key genes involved in neuronal cell growth and muscle formation, and the identification of cellular factors that suppress the ability of a mycobacterium to thrive inside cells.

JNKs respond to cellular stresses, and other signals, by modulating gene expression through phosphorylation of specific transcription factors. Dr. Perrimon’s lab performed a combinatorial high-throughput RNAi screen that was coupled to a fluorescence resonance energy transfer (FRET) output. The RNAi screen was designed to interrogate the JNK signaling circuit, while minimizing the number of false negatives, to find proteins that modulate this signaling pathway. These experiments uncovered classes of genes that affect JNK signaling, including various kinases and constituents of apicobasal polarity complexes.

Dr. Perrimon also studied the genetics of Drosophila muscle development. The lab used RNA interference to screen for genes that are required for muscle differentiation. The lab found that the iron chelating protein ferritin plays an important role in this process.  

Sarcopenia refers to the progressive loss of muscle mass that occurs with aging. We are currently investigating the full range of molecular and/or systemic mechanisms that contribute to a fly model of sarcopenia.  A. Wildtype somatic muscles display regular arranged sarcomeres.  B. Muscles expressing transgenic RNAi to various mitochondrial proteins display a reduction in size and diminished muscle strength. 

Biological Mechanisms and Pathways

• Cell morphology •
• Development •
• Genetics •
• Gut •
• Gut stem cells •
• Muscle growth •
• Neural outgrowth •
• Oncology •
• Signaling network
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Cancer

• Cancer •
• Oncology
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Disease Mechanisms

• Cancer •
• Disease genes
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Research Tools and Instrumentation

• Drosophila •
• Drosophila RNAi Screening Center
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Therapeutic Discovery Tools and Assays

• Cancer •
• Drosophila •
• High throughput RNAi •
• In vivo small molecule screening
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