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Pharmacogenomics Ch 9 pg 232

Pharmacogenomics Ch 9 pg 232. Pharmacology + Genomics How genome affects body response to disease, drugs People inherit/exhibit differences in drug : Absorption Metabolism and degradation of the drug Transport of drug to the target molecule Excretion of the degradation products.

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Pharmacogenomics Ch 9 pg 232

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  1. Pharmacogenomics Ch 9 pg 232 • Pharmacology + Genomics • How genome affects body response to disease, drugs • People inherit/exhibit differences in drug: • Absorption • Metabolism and degradation of the drug • Transport of drug to the target molecule • Excretion of the degradation products

  2. Goals of pharmacogenomics Use drugs better and use better drugs 1 AERS = Adverse Events Reporting System. This system managed by the U.S. Food and Drug Administration (FDA) contains over four million reports of adverse events and reflects data from 1969 to the present.

  3. GOALS • Dosage and drug specific to individual • Get it right first time • Create individual metabolic profile • Screen • presymptomatic • carriers • preimplantation, prenatal, newborn • disease susceptibility

  4. Barriers • Complexity – there are millions of SNPs • Which genes affect drug response? • Disincentive for companies $$ for small population • Educating physicians in genetics

  5. Will be commonplace in the doctors office • Genetic ID cards? • Certain diseases have gene expression “signatures”

  6. SNPs Chapter 8 pg 192

  7. DNA polymorphisms • People differ in nucleotide sequence • Coding sequences • Non-coding sequences (most) • Used as DNA markers • Evolution • To identify individuals • To diagnose disease • To diagnose genetic predisposition • Potential of individual to develop disease based on hereditary factors

  8. Can assist in The study of how non-genetic factors interplay with genetic

  9. SNPs = Single nucleotide polymorphisms(handout and CH 8 pg 270) • DNA sequence variations due to a single nucleotide in the genome • Occur ~1/300 bases in human genome • ~ 90% of all human genetic variation • Effort underway to map all human SNPs (~3 million) What is the size of the human genome in base pairs?

  10. SNPs Albuterol and SNPs Utah

  11. Many SNPs have no effect on cell function • Others could: • cause disease • predispose • influence disease progression • influence response to a drug

  12. SNP Read the gel results

  13. Tumor gene Find the SNP

  14. HapMap project • Haplotype • SNPs that tend to be inherited together. • Association studies

  15. DNA Microarrays pg. 239 Microarrays =small, glass slide spotted with short ssDNA sequences from ~20,000 different genes at fixed locations oligonucleotides ~20 bases single stranded

  16. Skin cancer microarray animation • Obtain samples • blood, tissue, tumor etc. What is the difference in gene expression in normal versus cancerous tissue?

  17. 2,3. Isolate mRNA • Expressed genes only • Quantitative 4. Reverse transcribe mRNA to cDNA • cDNA more stable than mRNA • Fluorescently labeled nucleotides used

  18. 5. Coat microarray chip with tagged cDNAs Hybridization - Immobilized target oligos found by probe DNA (the cDNAs) and nucleotides hybridize Transcriptic microarray (vs. genomic) You tube phg foundation plants

  19. 6. Scan for fluorescence

  20. GREEN =Control DNA, cDNA derived from normal tissue hybridized to oligo DNA.RED = Sample DNA, cDNA iderived from diseased tissue hybridized YELLOW = combination of Control and Sample DNA, both hybridized equally to target DNA.BLACK =neither Control nor Sample DNA hybridized . . Yeast flash animation

  21. Case study microarray • 76 patients with acute myeloid leukemia • DNA microarrays of 23,040 genes used to study gene expression . • Identified 63 overexpressed genes and 373 suppressed genes Among the over- and underexpressed genes, 28 were found to have different expression levels between patients who responded to chemotherapy and those who did not respond. (!) • 40 of 44 patients with a certain expression pattern underwent remission. • Compared 3of 20 patients in the other group. • Similar investigations are being undertaken in many other diseases, with the common goal of being able to predict therapeutic response prospectively through genomic methods, thereby allowing physicians to create far more specific and personalized treatment plans. http://radiology.rsna.org/content/231/3/613.full

  22. 2011 Microarrays and molecular markers for tumor classification Brian Z Ring and Douglas T Ross Human cancers have been classified according to tissue of origin, histological characteristics and, to some extent, molecular markers. Clinical studies have associated different tumor classes with differences in prognosis and in response to therapy. Measurement of the expression of thousands of genes in hundreds of cancer specimens has begun to reveal novel molecularly defined subclasses of tumor; some of these classes appear to predict clinical behavior, while others may define tumor types that are ripe for directed development of therapeutics.

  23. The future (and present) • Transcriptome • Collection of all RNA transcripts (m, t, rRNA) • Tissue specific gene expression • Which genes are on/off • Varies with cell type, environment, disease, etc.. • Use microarrays

  24. The transcriptome includes transcribed: • coding sequences • non-coding sequences <5% of human genome is transcribed

  25. Metabolome • All the small molecules involved in metabolic pathways • 3000 common metabolites in body tissues and biofluids • Dynamic!

  26. Proteome • All proteins in the cell • Larger than the genome • Alternative splicing • Post translational modification • Different proteins are found in different cells • Why proteins • Catalyze chemical reactions • Mount an immunological response to infection • chemical messengers to regulate growth, development, reproductive function, and metabolism.

  27. Microbiome • Human gut and how it changes with disease • 10X more bacteria in/on human body than human cells

  28. 600 species in oral cavity (most uncultivated, unnamed!) • Over 1000 species in human gut • Influence development, breakdown and absorption of nutrients , immunity, physiology • Study microbes as community

  29. Recent articles • Gut bacteria in Japanese people borrowed sushi-digesting genes from ocean bacteria • The bacterial zoo in your bowel • Gut bacteria – fat or thin, family or friends, shared or unique • Human gut bacteria linked to obesity • Divided by language, united by gut bacteria – people have three common gut types • Gut bacteria recap the evolution of apes • Gut bacteria change the sexual preferences of fruit flies • You are what you eat – how your diet defines you in trillions of ways • Baby’s first bacteria depend on route of delivery • The Effects of Circumcision on the Penis Microbiome • Characterization of the Oral Fungal Microbiome (Mycobiome) in Healthy Individuals

  30. Gnotobiotic mouse models • born, removed from the mother by C-section in sterile environment • Can be “humanized”

  31. Our colons harbor trillions of microbes including a prominent archaea, Methanobrevibacter smithii. To examine the contributionsof Archaea to digestive health, we colonized germ-free mice with Bacteroides thetaiotaomicron, an adaptive bacterial forager of the carbohydrates that we consume, with or without M. smithii

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