54th annual meeting of TS in Seattle

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54th annual meeting of TS in Seattle

  1. 1. Education Course 1 : Frontiers in Developmental Biology  Embryo and Tumors : The Relevance of Teratology Tumor : ~ invasion Embryo : road map “two cell ~ message sent by inducer” BC1750 함무라비 – cyclopia 1553 Paracelsus 1941 Greg – Congenital rubella syndrome 1959 Minamata bay 1960 Teratology Society founded 1961 Thalidomide episode 1970 ~ Gene-Enviromental cause
  2. 2. Effects of the Microbiome on embryonic and postembryonic development Microbiome? Oral streptococcus, vaginal lactobacillus, genital herpes simplex, varicella zoster, Cervical HPV etc. Microbiome is structured predominantly based on diet rather than habitus Diet can partially rescue a dysbiotic microbiome Maternal diet can persistently affect the developing microbiome Dietary alterations determine if an organism is commensal(symbiotic) or pathogenic(dysbiotic) What does this mean for disease treatment? - Dietary changes as a means for treating pathogenic bacteria? How does bacterial metabolism based on dietary alterations influence our metabolism and disease?
  3. 3.  Genomic approaches to understanding Normal and Abnormal Brain development: From Human to Animal models and Back Holoprosencephay as an example Midline defect of the developing forebrain and face Prevalence : 1 in 250 early embryo 1 in 10,000 live born infants ~ 1 in 100,000 children >1 year
  4. 4. Phenotype : extremely variable
  5. 5. HPE start? Human : Cyclopia take place before lateral movement of optic primordia at day 18 HPE : Environamental causes Most common teratogen : PGDM 1% risk Alcohol, retinoic acid Cholesterol lowering agent Heritable causes Cytogenetic abnormalities (25-50%) Trisomy 13 Microdeletions (10-20%) Single gene mutations : syndromic and non-syndromic
  6. 6. Clinical presentation Neurologic : developmental delay, epilepsy, hypotonia, spasticity Endocrine : DI, GH deficiency, adrenal hypoplasia, hypogonadism Oromotor dysfunction : feeding and swallowing difficulties require gastrostomy tubes Dysautomatic dysfunction : instability of BT, heart and breath rate Genetic counseling Challenges : phenotypic variablity, genetic heterogeneity, high risk of recurrence(13%)
  7. 7. The Role of Cilia in Development
  8. 8. The Role of Cilia in Development
  9. 9. The Role of Cilia in Development
  10. 10. The Role of Cilia in Development
  11. 11.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  12. 12.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  13. 13.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  14. 14.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  15. 15.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  16. 16.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  17. 17.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  18. 18.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  19. 19.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  20. 20.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  21. 21.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  22. 22.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  23. 23.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  24. 24.  The Role of Nutrition in Embryo & Fetal development Maternal nutritional status is a key modulator of embryonic and fetal development
  25. 25. Session 2: Mechanism of Abnormal Embryonic Development  Oxidative stress in Abnormal Embryonic and Fetal Brain Development
  26. 26. Session 2: Mechanism of Abnormal Embryonic Development  Oxidative stress in Abnormal Embryonic and Fetal Brain Development
  27. 27.  Epigenetic Marks in Germ cells and Embryos Epigenetic marks 1. DNA methylation 2. Histone modifications 3. Non-coding RNAs(miRNA,,,)
  28. 28.  There is increasing evidence that changes in DNA methylation, histone modifications and non-coding RNA transfer heritable information to the offspring.  Epigenetic modifications have been identified as factors in a variety of human diseases.  They are likely to play a key role in mediating the adverse effects of a number of environmental exposures on development.
  29. 29. Cellular signal transduction pathways
  30. 30. Cellular signal transduction pathways
  31. 31. Cellular signal transduction pathways
  32. 32. Cellular signal transduction pathways
  33. 33. Cellular signal transduction pathways
  34. 34.  Signal transduction pathways mediate an organism’s response to its internal and external environment  Many embryotoxic compounds disrupt normal signal transduction pathways  Disruption of signaling pathways can alter transcription factors and change gene expression, or can interfere with other cellular process  Signaling pathways are complex and interact in networks Main points
  35. 35. Gene Regulatory Networks(GRN) Types of biological networks : • Transcription factor-binding networks • Protein-protein interaction networks • Protein phosphorylation networks • Metabolic interaction networks • Genetic & small molecule interaction networks
  36. 36. GRN? “The body plan of an animal, and hence its exact mode of development, is a property of its species and is thus encoded in the genome. Embryonic development is an enormous informational transaction, in which DNA sequence data generate and guide the system-wide spatial development of specific cellular functions… GRN provide system level explanations of developmental and physiologic functions in the terms of the genomic regulatory code.” GRNs offer a mechanistic view of how the embryonic body plan is formed through lineage specification, differentiation, and morphogenesis”
  37. 37. Josef Warkany Lecture : KNUDSON TB – Developmental system biologist (EPA) Teratology V2.0 : Building a Path Forward Birth defect, gene, gene-evironment, research, understanding, fund Push the boundaries : Complex embryogenesis Big data : developmental pathway, process, toxicities Computational system biology : simpler : predictive and mechanistic understanding of teratogenesis
  38. 38. Systems Medicine and Proactive P4 Medicine : A revolution in Healthcare Ex)Prion accumulation- Glial activation - Synaptic degeneration- Neuronal cell death Lung mass - lung cancer/ benign D/Dx Personal health data, Genome, Biomarkers(proteins)--- Big data--- System biology Wellness Wellness Disease Time P4 : Predictive, preventive, personalized , participatory  Digital medicine for individual patient  Business plan  Emerging wellness industry(Microsoft) Hood L. : John’s H University, System biologist Special lecture
  39. 39. March of Dimes Symposium Advances in Early Diagnosis of Birth Defects and Adverse Perinatal Outcomes Smart skin sensors and Analytics in the Cloud to Advance the Frontiers of Wearable Health Dr. Coleman : Flexible skin-mounted wireless electronics + Multi-modal analytical algorithms in Cloud Big data ----+ small, relevant data ----+ clinician
  40. 40. Screening for Birth Defects and Teratogen risks with ultrasonography in Early Gestation Prolonged Doppler imaging : potential embryonic effects Early US for validate Ix : Gestational dating… Abortion 의심 시 7-10일에 repeat Slow heart rate – poor prognosis, but, range dramatically between 7-12wks. Maternal obesity : 20% lower detection of fetal anomalies
  41. 41. Role of First Trimester Fetal Echocardiography in the Identification of Birth Defects Early fetal echocardiogram : high risk group- 3 early markers of congenital heart anomaly : Increase NT, abnormal ductus venosus flow, tricuspid regurgitation additional markers : cystic hygroma, other anomalies Ix of Echocardiogram: Retinoid, Lithium, Trimethadione , Paroxetine, Alcohol (by AIUM, ACOG 2013) <14 weeks : >75% of standard cardiac views Sensitivity in 1st trimester : 10% in low risk population, >50% in high risk group For early reassurance Screening and diagnostic tools needs further evaluation Simpson LL, Columbia University
  42. 42. Fetal MRI As an Adjunct to Second Trimester US JOLLEY JA, U. of Washington, Seattle Fetal MRI 도움: CNS, facial anomalies, tumors, mass of neck and thorax US 한계 : reverberation artifact, Poor position, oligohydramniosis, obesity <18주 : little benefit 21-22주 : useful adjunct >3기 : optimal
  43. 43. Epigenetic Mechanisms in Intellectual Developmental Disabilities Epigenetic mechanism : Alteration in chromatin structure– regulate gene expression Do epigenetic mechanisms operate in behavioral memory formation? 1. Contextual fear conditioning triggers alterations in hippocampal DNA methylation and histone post-translational modifications 2. Inhibitors of DNA methylation block both hippocampal long-term presentation and associate learning in vivo 3. Remote contextual fear memory is associated with persisting changes in DNA methylation in the Anterior Cingulate Cortex, and DNA methyltransferase inhibition can reserve established remote memory 4. Histone acetylation increases in memory formation, and histone deacetylase(HDAC) inhibitors enhance both memory formation and hippocampal long-term potentiation.
  44. 44. Epigenetics Environmentally-induced Epigenetic Trans-generational Inheritance of Disease: Ancestral Ghost in Your Genome Trans-generational effects of environmental toxicants Sensitive period : during embryonic gonadal sex determination – germ line is undergoing epigenetic programming & DNA methylation Endocrine disruptor( fungicide, vinclozolin, BPA, phthalate, DDT, dioxin et al) Increase adult onset disease : infertility, ovary disease, cancer, obesity Trans-generational(F1, F2, F3 and F4 generation) by permanent altered DNA methylation of the germ line New paradigm in disease etiology that is relevant to other areas of biology such as evolution
  45. 45. Chromatin Remodeling , miRNAs, and Determination of Neurogenic cell fate miRNA : regulate gene expression by post-translationally repressing their target gene Brain enriched miRNA : miR-9/9* and miR-124 (neurogenic properties) human skin fibroblasts - post-mitotic neuron Hypothesis : transcription factors enriched in specific brain regions – guide the miRNA mediated neuronal conversion into specific neuronal subtype ex) transcription factors enriched in the striatum fibroblast – striatal neurons Demonstrate : miR-9/9* - miR-124 and transcription factors to generate specific neuronal subtypes
  46. 46. FAS(Fetal Alcohol Syndrome) Jones KL Retrospective look at 40 yrs of FAS FASD : spectrum of defects by prenatal alcohol exposure FAS : growth deficiency, microcephaly, characteristic facial abnormalities, neurodevelopmental defects ARND(Alcohol related neurodevelopmental disorder) : mild end lack the pattern of structural and growth deficits Issue : intervention and prevention DSM 5 Appendix
  47. 47. The Impact of Spina Bifida on Individuals, Families, and Society Whiteford ML, UK SB : life time cost – 620,000$ America : folic acid fortification Europe : 2ndary prevention by termination 1965 Hibaard Lancet 2007 CRC? 2011 No association with CRC 2014 Level of FA, Debate in house of Lords
  48. 48. Accelerating the pace of preventing Sina Bifida F and Anencephaly F 1991, unambiguous evidence of prevention of NTD 1998, 1.4ppm in USA, 1.5ppm in Canada Thalidomide – 10,000 victims NTD- 180,000 a year TS & ETS : all governments require folic acid fortification. Safety : 15mg safe by Goodman %Gilman 1996 2006 ???????? 2013
  49. 49. Accelerating the pace of preventing Sina Bifida F and Anencephaly F
  50. 50. [Teratogen update] Teratology and public health: working together to make recommendations for pregnant women in the face of uncertainty Weighing Risk & Benefit Benefit of intervention 》 Potential risk of harm 1. Rubella vaccine developed (1969) --- adolescent vaccine(UK) Children vaccine(USA) Prenatal test & postpartum vaccine(1984) 2. Folic acid potential risk : mask of Vitamin B12 deficiency, Pregnancy loss, Twining, Colon cancer, Dementia 1992 recommendation: 400mcg/d 1998 Fortification : 27% reduction of NTD(US) 3. Influenza : 5% death in pregnant women with influenza Prophylaxis : Pregnant vaccine protect : up to 6month Tx of influenza : Tamiflu + Acetaminophen
  51. 51. TH Shepard 감사합니다^^

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