HUG-CELL – Summary
Summary
The CEPID: Human Genome Research Centre at São Paulo- CEPID I, was initiated in 2000, prior to the first public release of the human genomesequence, with the intention of increasing our understanding and treatment of the most prevalent genetic diseases in Brazil. During CEPID-I weidentified 15 novel disease-related genes, investigated genotype-phenotype correlations for several genetic disorders and introduced stem-cell research, resulting in 392 peer-reviewed papers(some highly cited) and two patents. These investigations, and in keeping with the unexpectedly large amount of genetic variation exhibited by new sequencing technologies,demonstrated that the one mutation-one diseasemodel did not explain the aetiology of several of the allegedly Mendeliandiseases we studied. It is our aim during CEPID-II to investigate how synergistic effects between multiple mutations, the environment, including disruptions in non-coding genetic and epigenetic regulatory systems, modulatephenotypic diversity.
Over the last 40 years the Department of Genetics and Evolutionary Biologyat USP has assembled aunique collection of data from over 100,000 family members with neuromuscular, cranial-facial, intellectual disability, deafness, autism spectrum disorders (ASD), obesity, and other complexgenetic disorders (the largest in Latin America).The range of diseases has nowbeen extended to include neurodegenerative disorders (ALS, Parkinson), ageing (Cockayne syndrome) and DNA damage (XP). Moreover, approximately 50% of all current research activities within CEPID I involve stem cells (SC)with the ultimate aim of amelioratingsome of the major conditions seen in our genetics clinic.
Thisproposal focuses on development, degeneration and ageing in various genetic diseasesand will compare this to healthy ageing. Enormous technological improvements in DNA sequencing during the last decadenow enableresearchersto usebrute-force NGSfor diagnosis and counselling of many genetic diseases.Efficient access to NGS facilities is a common need for most of the projects in this proposal and an absolute necessityto remain competitive at highinternational level and to develop the genetic services that Brazil requires.Much of the proposed research will utilizepatient adult derived or induced-pluripotent SC(iPSC) to elucidate the changes in gene expression and differentiation potentialassociated with the genetic disorders under investigationin our centreand to assess the potential of SC therapies for the same disorders.
Various evidences point to a narrow dividing line in growth characteristics between SC, cancer cells and cancer SC:we will compare the growth and differentiation characteristics of cancer SC to their SC counterparts, including genome instability, telomere length, and epigenetic modification, not only in the proposed cancer/cancer stem cell analysis, but also in SC ageing studies. A cell repository primarily composed of adult SC from patients with genetic disorders and normal controls has been established and is undergoing further expansion.We will extend our studies on the differences in longevity, growth and differentiation potential of SC in vitroand in vivo, since there may be significant differences between organsand/orindividuals for a given type of SC.
Pre-clinical studies usingwell-defined animal modelsmimicking diseases such as Parkinson,epilepsy, ALSand Alzheimer,as well as various muscular dystrophies, including canine DMD,will be undertaken.Complementary models based on yeast will also be used to investigate protein function and aspects of post-translational modificationthat lead to disease manifestation in humans.
Population association studies will be undertaken using SNP and CNV screensin complex disorders, including cleft lip/palate, autism, obesity and hypertension, to identify candidate genes and how combinations of mutations lead to these complex phenotypes. In the case ofa putative gene pathway link between ASD and obesity, we will approach this by generating knock-down models in Drosophila and zebrafish,as well as human iPSC.
CEPID II includes an ambitiouspopulation study of ageing(project 80+).Brain MRI data and exome variability will be analyzed in a cohort of at least 1000 individuals older than 60 who have been followed since 2000 andwill be compared to 1000 healthy persons older than 80. The extent to which brain modifications are present will also provide insights into incipient Alzheimer disease and other neurodegenerative diseases. Further, on-going studies on genome stability, DNA repair and intracellular trafficking in patients or animal models will enhance our understanding of degenerative brain phenotypes at the cellular and molecular levels.
CEPID I created important research opportunities and a spatial and equipment infrastructure that would have been impossible to match using alternative funding mechanisms. Importantly, it provided the flexibility to introduce new scientific approaches, such as SC research, in a timely fashion; this is critical given the extremely rapid rate of change in human genetics. We intend to build upon these successes by further optimising inter-group synergy as well as research collaboration with othernational CEPIDs and international groups, leading to increasedpublication impact.
Research duringCEPID Iled to expansionof our Genetic Counseling (GC), diagnostic services and implementation of several core services made available to the scientific community, including: sequencing, genetic testing,array CGHetc.Under CEPID II, we will expand these services and expect to define new disease targets from our current research projects that can be used in drug screening in personalized medicine;thisdevelopmentshould alsostrengthen our ties with industry.
CEPID I fosteredgenetic education at USP,high schools, and provided outreach to the general public on topical genetic themes, which we willcontinue and expand.In particular,obligatory weekly seminars and work presentations for all CEPID IIgraduate studentswill begiven in English toimprove their language skills, increasegeneral knowledge and sense of integration. We willproduce science kits enablingyoung people to understand genetic principles through experimentation. New lab space will be created for national and internationaltraining courses, includinganinternational stem-cell course in collaboration withBritish scientists.
Our proposal for a center integrating human genome and stem-cellstudies in genetic disordersis an unique combination in Brazil and one of the most promisingscenarios to improve understanding of genetic disease etiology and permit entry into the long-anticipatedera of21st century treatment.
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