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Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors

Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors. RAUL A. BASTARRACHEA, M.D. Staff Scientist Department of Genetics TEXAS BIOMEDICAL RESEARCH INSTITUTE San Antonio, Texas, USA E-mail: raulbs@TxBiomedGenetics.org. ANUNCIO PRELIMINAR

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Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors

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  1. Genomics and Transcriptomics: Finding genes for obesity-related CVD risk factors RAUL A. BASTARRACHEA, M.D. Staff Scientist Department of Genetics TEXAS BIOMEDICAL RESEARCH INSTITUTE San Antonio, Texas, USA E-mail: raulbs@TxBiomedGenetics.org

  2. ANUNCIO PRELIMINAR V Curso Internacional sobre Obesidad en Español SAN ANTONIO, TEXAS 2012 OBESIDAD Y METABOLISMO DEL TEJIDO ADIPOSO: CONCEPTOS ACTUALES (De sus bases biológicas a su tratamiento clínico-farmacológico integral) Tema Central: LA CIENCIA DE LA SACIEDAD Y EL APETITO II Fecha: Jueves 15, Viernes 16 y Sábado 17 de Noviembre de 2012 Informes: office@amcien.com www.amcien.com

  3. Current treatment programs for obese individuals are not very effective over the long term, leading to the common wisdom that persons who successfully lose weight will regain it all within 5 years. Brownell KD, Jeffrey RW. Improving long-term weight loss: pushing the limits of treatment. Behav Ther 1987;18:353–74.

  4. Ghrelin-PYY-OXM-GLP-1-Incretins-Amylin

  5. Filtros Biológicos • FILTRO CORTICAL: Se integran las señales en la corteza cerebral provenientes de estímulos asociados a los alimentos y al hambre (olor, visión, sabor, etc). • FILTRO EMOCIONAL Y DE PLACER: Incluye los centros dopaminérgicos y canabinoides localizados en la amígdala, el sistema mesocorticolímbico y el núcleo acumbente cerebral donde se integran las señales de ingesta por recompensa y adicción. • FILTRO METABÓLICO: Incluye el centro del hambre del hipotálamo y las vías catabólicas y anabólicas y sus conecciones periféricas con los factores de saciedad gastrointestinales y las señales de adiposidad representadas por la leptina y la insulina en la grasa y la amilina en el páncreas. Zheng, H. et al. Physiology 23: 75-83 2008

  6. NON-HUMAN PRIMATE STUDIES Metabolic profiling in baboons Pharmacogenomics of hunger and satiety Euglycemic-Hyperinsulinemic clamp in baboons Omentectomy project – Fatty acid kinetics Type 2 diabetes through surgery – hemipancreatectomy Development of an obese baboon colony

  7. Reversal of STZ-induced diabetes using ultrasound destruction of microbubbles for the delivery of genes to the baboon pancreas. 1251PC Protocol/2011/Grayburn-Bastarrachea PHENOTYPE MEASUREMENTS

  8. Identificación de la secuencia de DNA A U T C G Búsqueda de polimorfismos asociados a fenotipos

  9. Disease risk Genome-Wide Scan ~ 363 markers 9.5 cM = 9.500 Kb ~9.5 cM Quantitative Linkage Analysis Phenotypes: Circulating Proteins Physiological Parameters

  10. QTL in Chr 16

  11. mutation SNPs 1. pedigrees 4. positional candidate gene variants 3. Association LD mapping 5. Function/activity Microarrays Expression Homology Tg/Ko/RNAi Searching for Genes for Complex Genetic Disease: The Standard Model 2. Linkage (allele sharing)

  12. PROGRAMA PARA LA INVESTIGACIÓN GENÉTICA DE LAS ENFERMEDADES METABÓLICAS RELACIONADAS CON LA NUTRICIÓN A NIVEL POBLACIONAL Bases Genómicas del Metabolismo Posprandial San Antonio CONSORCIO Chihuahua Monterrey* Mérida* San Luis Potosi Ciudad Victoria DF Guadalajara Veracruz GEMM Family Study Genética de las Enfermedades Metabólicas en México Morelia Cuernavaca Oaxaca

  13. GENOMICS DNA (30,000) Transcription – mRNA (100,000) PROTEOMICS Polypeptide chain – Modification – Functional Protein (1,000,000)

  14. Illumina Beadscan GX Confocal laser scanning system Resolution, 0.8 micron Two lasers 532, 635 nm Supports Cy3 & Cy5 imaging Fully automated operation Supports genotyping, expression and proteomics applications High throughput (whole genome) gene expression Whole genome 48,000 probe array • Fibre optic bead (Illumina) technology facilitates rapid measurement of genome-wide gene expression profiles • Software to visualize and summarize large data sets in graphical format Increased sensitivity, high throughput • Illumina Beadscan GX technology detects expression of 48,000 transcripts simultaneously

  15. Gene Expression: Preliminary Results • Transcriptional profiles on 1013 Mexican Americans from the San Antonio Family Heart Study • RNA extracted from stored lymphocytes • 22,120 detected quantitative transcripts • Of these, 16,028 are heritable • Developed new statistical methods for high dimensional biomarker/endophenotype search

  16. Gen Transcripción Traducción Modificaciones Post-traduccionales Función Interacción entre Genes y Nutrimentos

  17. La utilización lenta de los metabolitos es la huella digital del proceso patológico (disregulación molecular de nutrientes)

  18. GEMM Study: Monterrey Even in this very small sample we observed substantial correlation of expression across tissues.

  19. Ingenuity Pathway Analysis (IPA) IPA functional class assignments for correlated transcripts: IPA is a powerful curateddatabase and analysis system for understanding how proteins work together to effect cellular changes. We use this system to classify the correlated sets by gene function. This figure shows the top ten functional classes for each focal transcript. There is considerable consistency in functional assignment across tissues.

  20. FUTURE APPROACH: Genetically-based programs COMPLEMENTING “Environmentally”-based programs of prevention and therapy for Common Complex Diseases: Obesity and T2DM

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