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Oxford Hair Foundation Genetics of Scalp Disorders

Oxford Hair Foundation Genetics of Scalp Disorders. Thomas L. Dawson, Jr., Ph.D. What is Dandruff?. Dandruff Physiology. Dandruff flakes are the opposite of dry skin. Dandruff, 27,000X. Leg skin, 21,600X. Dandruff Physiology. Dandruff scalp. Non-Dandruff. Dandruff Physiology.

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Oxford Hair Foundation Genetics of Scalp Disorders

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  1. Oxford Hair FoundationGenetics of Scalp Disorders Thomas L. Dawson, Jr., Ph.D.

  2. What is Dandruff?

  3. Dandruff Physiology Dandruff flakes are the opposite of dry skin Dandruff, 27,000X Leg skin, 21,600X

  4. Dandruff Physiology Dandruff scalp Non-Dandruff

  5. Dandruff Physiology Non-Dandruff Dandruff scalp 75K mag. 94 K mag.

  6. What is dandruff – summary • Dandruff is a less severe form of seborrheic dermatitis • Dandruff is the opposite of dry skin: • excess lipids • no desmosomes

  7. Dandruff Microbiology • Current hypotheses implicate microorganisms infecting the scalp, predominantly Malassezia fungi • Malassezia fungus is found on all scalps, but: • Malassezia actually consists of at least ten species, M. furfur M. pachydermatis M. sympodialis M. globosa M. obtusa M. slooffiae M. restricta M. dermatis M. japonica M. equi

  8. So then, Who is really there?

  9. Genomics I - Application of Genetic Tools to Dandruff Aetiology • M. furfur or P. ovale is frequently cited as the dandruff causal organism, based on culture methods • Genomics-based techniques identify the actual culprits, M. restricta and M. globosa

  10. Assess Malassezia as they are in situ sympodialis restricta pachy slooffiae obtusa globosa furfur Isolate DNA PCR amplify Sample Why Genomic Speciation? No bias on culture!

  11. 80 60 40 20 furfur obtusa restricta globosa slooffiae sympodialis Non-Malassezia Fungi pachydermatis Malassezia Species on Human Scalp ASFS <10 (N=24) ASFS >24 (N=46) Frequency (% of N) No fungidetected

  12. restricta? globosa? So, who’s the culprit?

  13. Mechanism How do Malassezia restricta and globosa cause dandruff?

  14. Malassezia Lipids Lipase Expression n o i t a r e f i l o r P Triglyceride hydrolysis fatty acid consumption Dandruff flaking Inflammatory reaction fatty acid penetration Hyper-Proliferation Caused by Inflammation Sebaceous

  15. Oleic Acid Clinical Data Dandruff Sufferers 7.5% OleicAcid Placebo vehicle • Oleic acid, alone, can induce dandruff in human subjects 1 Flaking 0 - 1 3 4 5 6 7 8 9 Days Treatment

  16. 100 2.5 90 80 2 70 Percentage of Subjects 60 1.5 Lipase Activity 50 40 1 30 20 0.5 10 0 0 M. furfur M. obtusa M. globosa M. restricta M. slooffiae M. sympodialis Which Malassezia Species Causes Dandruff? Malassezia globosa is mostly likely the causative agent based on prevalence + activity

  17. Genomics II - Cloning of the M. globosa Lipase H2N-GRGGSST DQPVANPYNT KEISLAAGLV QQTYCDSTEN GLKIGDSELL YTMGEGYARQ RVNIYHSPSL GIAVAIEGTN LFSLNSDLHD AKFWQEDPNE RYIQYYPKGT KLMHGFQQAY NDLMDDIFTA VKKYKKEKNE KRVTVIGHSL GAAMGLLCAM DIELRMDGGL YKTYLFGLPR LGNPTFASFV DQKIGDKFHS IINGRDWVPT VPPRALGYQH PSDYVWIYPG NSTSAKLYPG QENVHGILTV AR Yellow –peptide sequence Red - conserved active site Pink – peptide sequence

  18. Genomics III - The Future Comparative Whole-genome Analysis

  19. Some sequenced fungal genomes Saccharomyces cerevisiae – the “quintessential” fungus

  20. Some sequenced fungal genomes Ustilago maydis - Malassezia’s near neighbour

  21. Some sequenced fungal genomes Candida albicansa - common human pathogen

  22. Some sequenced fungal genomes Cryptococcus neoformans - another common human pathogen

  23. The Whitehead Initiative! 7 Fungal Genomes Sequenced 44 genomes proposed to be sequenced

  24. The problem • Fungal infections and fungal-related mortality is on the rise • Current anti-fungal therapies essentially rely on four gene targets

  25. Progress from functional genomics • Genomics research has defined new families of “essential” genes • Genomics research has developed new models to much more rapidly assess the effects of disruption of these essential targets

  26. Progress from functional genomics • Now, we have gone from four known targets to hundreds of targets in thousands of genes • The trick now becomes – what are the best of these targets, and how do we find new materials?

  27. Progress from functional genomics • New target identification: • Is the proposed target present in the genome? • Is the target relevant to the disease/disorder? • Is the target testable in a validated assay? • Is it expressed in situ?

  28. On the horizon • Fusion of human and fungal genome data, to decipher the communication between host and fungus • Replace anti-fungal technology with “normalization” technology!

  29. P&G Joe Kaczvinsky Charlie Saunders Tina Gemmer Yvonne DeAngelis Erin MacDonald Meredith Leland Kevin Johnstone Mariann Jenkins Collaborators Aditya Gupta, MD, PhD, MediProbe Labs, Canada Teun Boekhout, PhD, The CBS, The Netherlands Jim Kronstad, PhD, Univ. British Columbia George Smulian, Univ. Cincinnati, USA Bo Yuan, Ohio State, USA Pamela Troller, Augustana College, USA The Team

  30. Thank You

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