Peter Espenshade Department of Cell Biology Cellular Control of Metabolism Jürgen BergerMax Planck Institute Cells require tight regulation of metabolism to maintain homeostasis and viability ID: 1036502
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1. Measuring Cholesterol: From Man to Yeast and Back Peter EspenshadeDepartment of Cell Biology
2. Cellular Control of MetabolismJürgen Berger/Max Planck InstituteCells require tight regulation of metabolism to maintain homeostasis and viability.Metabolism = the chemical reactions in a cell or organismHomeostasis = control of a system keep it stable or constant
3. Hepatic ArteryHigh oxygenCentral VeinLow oxygenAdapted from http://www.siumed.edu/Cells Adapt to Their Environment to Maintain Homeostasis O2
4. Tumor Cells Adapt to Their Environment to Maintain HomeostasisSemenza, 2011Semenza, 2008
5. Control of Cholesterol and Fat SynthesisAcetyl-CoA, NADPH, O2, ATPCholesterol& FatCholesterol& FatSynthesisSREBP
6. SREBP Controls Synthesis of Cholesterol and FatKorn et al., J. Clin. Invest. 1998, 102:2050-2060.Normal LiverHigh SREBP
7. Loss of SREBP Prevents Diabetic Fatty LiverMoon et al. 2012 Cell Metab. 15: 240-246.
8. Talk OutlineYeast SREBP is controlled by oxygenSREBP is required for virulence of pathogenic fungi.What can this tell us about human cancer?
9. Conservation of SREBP in Fungi
10. SREBP Responds to Oxygen in FungiO2Gene expression requiredfor low oxygen growthSREBP[]
11. Control of Cholesterol and Fat SynthesisAcetyl-CoA, NADPH, O2, ATPCholesterol& FatCholesterol& FatSynthesisSREBPX
12. Conservation of SREBP in Fungi
13. Cryptococcus neoformansHuman opportunistic fungal pathogenInfects ~30% of patients with AIDS in Africa and Southeast AsiaCommon diseases: - meningoencephalitis - pneumonia
14. 21%O214%3%Hypothesis: SREBP is required for growth in animals.Cryptococcus neoformansJune Kwon-Chung – NIH, NIAID
15. SREBP is Required for C. neoformans Infection7 days post-infection via tail vein
16. Conservation of SREBP in Fungi
17. SREBP is Required for A. fumigatus Low Oxygen GrowthWillger et al. PLoS Pathogens 2008Wild-typesre1D
18. SREBP is a Conserved Virulence Factor and Antifungal Drug Target
19. Tumor Cells Adapt to the Environment to Maintain HomeostasisSemenza, 2011Semenza, 2008
20. Is SREBP a Therapeutic Target for Pancreatic Cancer?Tumor Hypoxia (Low O2)Cholesterol & Fat SynthesisTumor GrowthSREBP
21. CRISPR Knockout of SREBP Pathway
22. Is the SREBP Pathway a Therapeutic Target for Pancreatic Cancer?Tumor Hypoxia (low O2)Cholesterol & Fat SynthesisTumor GrowthSREBPDrugs
23. Yeast SREBP is controlled by oxygen and required for fungal pathogenesis.SREBP may be required for pancreatic tumor growth and a new therapeutic target for this devastating disease. - Studies of a simple yeast can provide important insights into human disease.Summary
24. espenshadelab.comFUNDINGAHN-JHU Cancer Research Fund CURRENT LAB MEMBERSRisa BurrSara Clasen He GuJiwon HwangMeredith McGuireSumana Raychaudhuri, PhDWei Shao, PhDShan ZhaoCOLLABORATORSC. neoformansJune Kwon-Chung – NIHPancreatic cancerAnirban Maitra – SKCCCZeshaan Rasheed – SKCCC