Stem cells in human genetic diseases - CETGEN

• Grant number: 08/57899-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2009
• End date: December 31, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: CNPq - INCTs
• Principal Investigator: Mayana Zatz
• Grantee: Mayana Zatz
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

This is a proposal to establish a reference centre for a stem cell bank from patients with genetic diseases and associated stem cell research linked to the largest center for the study of genetic disorders in Latin-America The major challenge behind all genome research is to understand how genes function and interact with each other. The understanding of gene function requires studies that integrate cytogenetic and molecular analyses, studies of gene structure and products, at both the RNA and protein levels, and the correlation of genetic and phenotypic variation. The latter is mainly carried out within the context of human genetic disorders. Furthermore, in terms of pathological variation, recent molecular studies have shown for a great number of genetic disorders, that patients with the same pathological mutation may have strikingly different phenotypes. In addition, several disorders involving growth, eating, and behavioral disturbances have epigenetic mechanisms involved in their etiology. Usually, the epigenetic changes are dependent on the sex of the parent-of-origin, resulting in differential expression of parental alleles during embryogenesis and subsequent development of the offspring. These observations only highlight the importance of other genetic and/or non-genetic factors in determining phenotypic expression. The search for modifying genes, which modulate gene expression, and determining the role of imprinted genes or other epigenetic factors is of utmost importance. The aim of these investigations is to enhance our understanding on genes responsible for genetic disorders and on mechanisms of origin and clinical effects of structural chromosome alterations. Primarily because of existing interests within the group of investigators of the Human Genome Research Center from (HGRC) USP, the major classes of genetic disease that will be covered by this application will involve neuromuscular, cranio-facial, neurodevelopmental, neurodegenerative and gonadal disorders. In addition an extra section on safety factors, teaching and out-reach of professional training on stem cell applications and collaborative projects with special attention to emerging groups in Espírito Santo, Paraíba, Minas Gerais, Ceará and Paraná will be part of the program. Towards this end we firmly believe that the use of stem cells derived from individuals with genetic disorders will greatly improve the depth and interpretation of our investigations. Muscle, osteoblast and neurons cells derived from stem cells obtainable from a variety of tissues, including dental pulp, umbilical cord, adipose tissue, menstrual blood, skeletal muscle or skin can be analyzed in vitro to study the effects of pathogenic mutations on genetic disorders and eventually to identify putative pathways available for therapeutic approaches. Our group has expertise in isolating and manipulating adult stem cells in vitro from different sources. In addition preclinical experiments in animal models are being conducted with promising results. Induced pluripotent stem (iPS) cells obtained from affected patients as well as embryonic stem cells derived from embryos carrying pathogenic mutations obtained from pre-implantation diagnosis are of particular interest. Furthermore, we are interested in understanding the parameters determining longevity, which is particularly relevant to the Brazilian population at present because of the rapid increase in life expectancy over the last two decades. The UNO estimates that the average Brazilian life expectancy will increase by 10 years to 79 years by 2050, and raises the question of, not whether but, how the health of this aging population is determined by its genetic composition. Anticipating a future need for research in this direction, we plan to start banking DNA and tissues samples from a wide range of healthy individuals above the age of 80 to facilitate this. The constitution of a stem cell bank containing samples derived from a wide range of patients with genetic disorders is of utmost importance for the development of research projects and defining potential avenues of therapy. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NASLAVSKY, MICHEL SATYA; YAMAMOTO, GUILHERME LOPES; DE ALMEIDA, TATIANA FERREIRA; EZQUINA, SUZANA A. M.; SUNAGA, DANIELE YUMI; PHO, NAM; BOZOKLIAN, DANIEL; MILKEWITZ SANDBERG, TATIANA ORLI; BRITO, LUCIANO ABREU; LAZAR, MONIZE; et al. Exomic variants of an elderly cohort of Brazilians in the ABraOM database. Human mutation, v. 38, n. 7, p. 751-763, JUL 2017. (11/17428-8, 98/14254-2, 13/08028-1, 08/57899-7)

MOREIRA, DANIELLE P.; GRIESI-OLIVEIRA, KARINA; BOSSOLANI-MARTINS, ANA L.; LOURENCO, NAILA C. V.; TAKAHASHI, VANESSA N. O.; DA ROCHA, KATIA M.; MOREIRA, ELOISA S.; VADASZ, ESTEVAO; CASTRO MEIRA, JOANNA GOES; BERTOLA, DEBORA; et al. Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy. PLoS One, v. 9, n. 9, SEP 25 2014. (13/08028-1, 08/57899-7)

GOMES, JULIANA P. A.; ASSONI, AMANDA F.; PELATTI, MAYRA; COATTI, GIULIANA; OKAMOTO, OSWALDO KEITH; ZATZ, MAYANA. Deepening a Simple Question: Can MSCs Be Used to Treat Cancer?. ANTICANCER RESEARCH, v. 37, n. 9, p. 4747-4758, SEP 2017. (13/08028-1, 08/57899-7)

ZATZ, M.; VIEIRA, N. M.; ZUCCONI, E.; PELATTI, M.; GOMES, J.; VAINZOF, M.; MARTINS-BACH, A. B.; GARCIA OTADUY, M. C.; BENTO DOS SANTOS, G.; AMARO, JR., E.; et al. A normal life without muscle dystrophin. Neuromuscular Disorders, v. 25, n. 5, p. 371-374, MAY 2015. (13/08028-1, 08/57899-7)