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Lecture 12 disturbances in growth and differentiation


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Lecture 12 disturbances in growth and differentiation

  1. 1. Disturbances in Growth and Differentiation <ul><li>Embryology </li></ul><ul><li>Teratology </li></ul><ul><li>Oncology </li></ul>
  2. 2. Embryology
  3. 3. Coordinated events <ul><li>Physiologic Stimuli </li></ul><ul><ul><li>Hormones </li></ul></ul><ul><ul><li>Growth factors </li></ul></ul><ul><ul><li>Nutrients </li></ul></ul><ul><li>Blood Supply </li></ul><ul><li>Tissue/Cell interactions (cell-cell communication) </li></ul>
  4. 4. Cell Differentiation and Regeneration <ul><li>The capacity for tissue repair following injury depends on the ability of the terminally differentiated cells to replicate and the presence of tissue stem cells </li></ul>
  5. 5. Renal Dysplasia vs. Chronic Renal Failure
  6. 6. Teratology
  7. 7. Teratology Study of Developmental Anomalies <ul><li>2% of live births have major abnormality </li></ul><ul><li>Up to 5% if minor abnormalities included </li></ul><ul><li>Cultural differences </li></ul>
  8. 8. Etiologies of Birth Defects
  9. 9. Cyclopia <ul><li>Veratrum californicum </li></ul><ul><ul><li>14th day of gestation </li></ul></ul><ul><ul><ul><li>protruding lower jaw, underdeveloped upper jaw, proboscis-like nose, cyclopia, hydrocephaly, other ocular defects </li></ul></ul></ul><ul><ul><ul><li>prolonged gestation </li></ul></ul></ul><ul><ul><ul><ul><li>hypothalmic-pituitary-adrenal axis </li></ul></ul></ul></ul><ul><ul><li>17-19 days of gestation </li></ul></ul><ul><ul><ul><li>tracheal stenosis </li></ul></ul></ul><ul><ul><li>28-31 days of gestation </li></ul></ul><ul><ul><ul><li>shortened metatarsal and metacarpal bones </li></ul></ul></ul>
  10. 10. Errors of Morphogenesis Developmental Syndrome
  11. 11. Developmental Syndrome <ul><li>Aborted minature foal </li></ul><ul><li>Hydrocephalus </li></ul><ul><li>Brachygnathia superior </li></ul><ul><li>Metacarpal-digital and metatarsal-digital varus </li></ul>
  12. 12. Errors of Morphogenesis Deformation
  13. 13. Arthrogryposis <ul><li>Cache Valley Virus </li></ul><ul><li>oligoamnios </li></ul><ul><li>Lupinosis </li></ul><ul><li>CNS malformation </li></ul>Errors of Morphogenesis Deformation
  14. 14. Spina Bifida
  15. 15. Spina Bifida
  16. 16. Cleft Palate
  17. 17. Relationship Between Genotype and Phenotype Epigenetic Events <ul><li>Histone de-acetylation </li></ul><ul><li>DNA methylation </li></ul><ul><li>Micro RNA </li></ul><ul><ul><li>Downregulation </li></ul></ul>
  18. 18. Interplay Between Environment and Genotype <ul><li>Carcinogens </li></ul><ul><ul><li>Chemical </li></ul></ul><ul><ul><li>Radiation </li></ul></ul><ul><li>Oncoviruses </li></ul><ul><ul><li>Papilloma </li></ul></ul><ul><ul><li>Lymphoma </li></ul></ul><ul><ul><li>Sarcomas </li></ul></ul><ul><li>Inflammation </li></ul><ul><li>DNA repair defects </li></ul><ul><li>Tumor suppressor gene defects </li></ul>
  19. 19. Mutations <ul><li>Genome mutations ( gain/loss of whole chromosomes) </li></ul><ul><li>Chromosome mutations (altered structure) </li></ul><ul><li>Single gene mutations </li></ul>
  20. 20. Cytogenetics
  21. 21. Types of Chromosome Mutations
  22. 22. Spectral Karyotyping
  23. 23. Molecular Diagnostics FISH- Interphase nucleus- Green probes for Chr 13, and Red for Chr 21 (trisomy 21) FISH- Multicolor FISH- Shows portion of chromosome 22q to chromosome 9
  24. 24. Microarray- Gene Chip (left) – used to sequence thousands of base pairs of DNA. Close up view of hybridization pattern of the microarray.
  25. 25. Single Gene Mutations <ul><li>Target genes </li></ul><ul><ul><li>Enzymes </li></ul></ul><ul><ul><li>Receptors </li></ul></ul><ul><ul><li>Structural proteins </li></ul></ul><ul><ul><li>Cell growth regulators </li></ul></ul><ul><li>Different mutations may have vastly different effects </li></ul>
  26. 26. Mechanisms of Single Gene Mutations Amino Acid Substitution Premature Termination Frameshifts
  27. 27. Diagnosis of Single Gene Mutations “ Molecular Pathology ”
  28. 28. Errors of Morphogenesis Sensitivity to Teratogenic Agents
  29. 29. Errors of Morphogenesis Agenesis vs. Aplasia
  30. 30. Errors of Morphogenesis Hypoplasia vs. Abiotrophy
  31. 31. Errors of Morphogenesis Dysraphism Spinal bifida and menigomyelocoele
  32. 32. Errors of Morphogenesis Ectopia
  33. 33. Errors of Morphogenesis Dystopia
  34. 34. Errors of Morphogenesis Dysplasia
  35. 35. Neoplasia
  36. 36. Disturbances of Cell Proliferation Epithelium Reversible Reversible Reversible
  37. 37. Cell Cycle G1/S Checkpoint- Cyclin D/CDK4, Rb, P53 G2/M Checkpoint- Cyclin A/CDK2
  38. 38. Cell Cycle-Stages <ul><li>G0- Resting Cells </li></ul><ul><li>G1-preparation for division(G for growth) </li></ul><ul><li>S- DNA synthesis </li></ul><ul><li>G2- Preparation for cell division </li></ul><ul><li>M- Actual mitosis </li></ul>
  39. 39. Cell types <ul><li>Non-Dividing </li></ul><ul><ul><li>Permanent G0 </li></ul></ul><ul><ul><ul><li>Neurons, Cardiac muscle, Skeletal muscle </li></ul></ul></ul><ul><li>Quiescent (Stable tissues) </li></ul><ul><ul><li>G0-G1 transition when stimulated </li></ul></ul><ul><ul><ul><li>Liver, kidney, pancreas, mesenchymal tissues, vascular </li></ul></ul></ul><ul><li>Continuously Dividing (Labile) </li></ul><ul><ul><li>Never in G0 </li></ul></ul><ul><ul><ul><li>Epithelia, Bladder, glands </li></ul></ul></ul><ul><ul><ul><li>Arise from tissue stem cells </li></ul></ul></ul>
  40. 40. Cell Cycle- Regulation <ul><li>Proto-Oncogenes </li></ul><ul><ul><li>Growth Factors, Transcription factors stimulated by growth factors or involved in signaling by growth factors </li></ul></ul><ul><ul><li>Necessary for progression through cell cycle checkpoints </li></ul></ul><ul><ul><ul><li>Cyclins, CDK’s, c-fos, c-jun- c-myc, PDGF, RAS </li></ul></ul></ul><ul><li>Tumor Suppressor Genes </li></ul><ul><ul><li>Monitor DNA damage and lead to arrest of cell cycle or apoptosis </li></ul></ul><ul><ul><ul><li>P53, Rb </li></ul></ul></ul><ul><li>DNA repair genes </li></ul><ul><li>Apoptosis genes </li></ul>
  41. 41. Cell Cycle
  42. 42. Cancer Genetics
  43. 44. THE END!