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«TITLE: HEREDOATAXIAS: ANALYSIS OF MITOCHODRIAL DAMAGE AS AN UNITARY PATHOGENIC MODEL • Nombre y apellidos del investigador principal Adriano ...»

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PEREZ DE GUZMAN EL BUENO

Equipo investigador (máximo 2 páginas): presentación de los miembros del equipo especificando su cualificación, experiencia y capacidad para llevar a cabo los objetivos del proyecto.

RESEARCH TEAM:

Adriano Jiménez Escrig, MD PhD (Principal Investigator) Antonio Sánchez Herranz, BS PhD Eulalia Bazán Izquierdo, BS PhD Diana Reimers Cerdá, BS PhD M. José Casarejos Fernández, BS, PhD Gloria Muñoz Martín, BS PhD LOCATION: Servicio de Neurología, Hospital Ramón y Cajal and Servicio de NeurobiologíaInvestigación, y Unidad Central de Apoyo en Genómica Translacional del Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). Madrid, España.

The research team has experience in reaching agreements with biotechnology companies for the exploiting the results, patent applications, etc. Regarding the dissemination of results the group maintains a continuous activity publications as well as participation in national and international conferences on degenerative diseases of the nervous system. The IP (Dr. Jiménez Escrig) participate regularly at training courses, conference presentations, lectures and dissertations.

The IP is responsible for the consultation of Neurogenetics in the Neurology Service of the Hospital Ramón y Cajal, performs clinical and molecular diagnosis of ataxias, hereditary dementias, familial amyloid polyneuropathy and cerebrotendinous xanthomatosis in the center.

He is expert in training on Neurogenetics, having tutored three PhD thesis on the subject (Alzheimer's Disease: Genetic Risk Factors for Alzheimer's Disease: Clinical and Epidemiological Study. Universidad de Alcalá, 2001, Dr. Baron; Study familial Parkinson's disease with high-density SNPs. Universidad de Alcalá 2009, M. Sagrario Manzano and cerebrotendinous xanthomatosis in Spain: mutations, clinical and therapeutic aspects.

Universidad de Alcalá 2010). This late was awarded with the Prize Alberto Rabano 2010 for the best thesis in Neuroscience. He is also director of the PhD courses: Basic and Clinical Neurogenetics, years 2002-2009. University of Alcala and Short Course on Neurogenetics, a short course aimed to train European young Neurologists.

Dr. Sánchez Herranz is an expert in cell biology studies regarding mitochondrial activity and ROS toxicity in neurodegeneration. He is currently the Manager Director of Unidad Central de Apoyo en Genómica Traslacional del IRYCIS-Hospital Ramón y Cajal.

Dr. Gloria Muñoz has an extensive experience as a specialist in Molecular Genetics collaborating with several research groups in different genetics laboratories throughout his career. During his postdoctoral training worked on projects to unravel the genetic basis of complex traits such as obesity, cancer and aggressive behavior in the University of Chapel Hill, North Carolina (USA). Currently she is in charge of the Unidad Central de Apoyo en Genómica Traslacional del IRYCIS-Hospital Ramón y Cajal where we will run the Next Generation Sequencing experiments.

Dr. Diana Reimers, Dr. Eulalia Bazán and Dr. M. Jose Casarejos belong to the Neurobiology Department of the Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), whose line of research is in the field of Cell Therapy and Regenerative Medicine. Dr. Reimers and Dr. Bazán posses high experience in identifying factors which promote proliferation, migration and neuronal differentiation of the stem-cells, and in studying its therapeutic potential in experimental models of neurodegenerative diseases. Dr. Casarejos is expert in cell biology studies regarding mitochondrial activity and ROS toxicity in neurodegeneration

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

The group has published four papers in international journals in 2010 on neuropsichiatric disease genetic studies, 5 items in 2011 and now has 2 published articles on next generation sequencing in 2012, and additional two articles are under review and a chapter book. Currently, they have 4 complete genomes and 28 exome in patients with different neurological diseases, being the Spanish center with more clinical experience in this area (see ref. 10-11).

The IP currently manages a multidisciplinary reference Unit for Ataxia and Spastic Paraplegia in the Hospital Ramón y Cajal. The group has an extensive research experience in experimental models of ataxia. Recently we have published an article in Stem Cells International on the benefit of the transplantation of human umbilical cord blood stem cells in an experimental model of ataxia. There are two submitted manuscripts on the same field and an additional one in preparation (detailed in CV).

There is also a training line of ataxia, with a PhD work on preparation (Lucia Calatrava Ferreras, Universidad Autónoma de Madrid, Facultad de Biológicas) tutored by Dr. Bazán and Dr. Sanchez Herranz, and several practicum and end of master projects on this line.

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

Medios disponibles y medios solicitados a la Fundación para realizar el proyecto We have the following media for carry on the project.





Clinical office with equipment, 2 PC computers with printer where we will perform the clinical assessment of affected, data collection and informed consent Laboratory for molecular biology with two thermal cyclers two micro centrifuges, two power supplies and electrophoresis tank, bathroom, oven, microwave, etc...

DNA extraction and NGS with PGM (Ion Torrent) will be held at the UCA-GT at Ramón y Cajal Institute of Health Research (IRYCIS).

The UCA-GT has been created entirely new in July 2012 and is fully equipped for next generation sequencing techniques offered by the unit. Laboratory area 1 has been designed to make it the automated extraction of nucleic acids, nucleic acid analysis and automated preparation of libraries intended for the sequencing service. The laboratory area 2 is divided into two zones, one main area to service NGS, and other office area with workstations for bioinformatics analysis. The UCA-GT has an automated nucleic acid extractor Chemagic MSM I (Chemagen, PerkinElmer) spectrophotometer Nanodrop 2000 an Agilent 2200 Bioanalyzer System TapeStation a Qubit 2.0 Fluorometer a massive sequencer Personal Genome Machine (PGM) (Ion Torrent ), an Ion Enrichment System and One Touch System. The UCA-GT features itself with the following small item: laminar flow cabinet with UV light for PCR, several microcentrifuge, centrifuge plate, vortex stirrer, pH meter, two thermal cyclers, 3 sets of micropipettes, heat block and equipment electrophoresis, refrigerators and freezers.

For the study of mitochondrial function with have:

Two Cell Culture Units, Spectrophotometry Unit, Centrifugation and Ultracentrifugation and Proteomics Unit (HPLC, FPLC and Maldi-Toff and Western blot) HPLC for determination of amino acids, catecholamines, glutathione, vitamins and other molecules Flow Cytometry Unit, Conventional and Fluorescence Microscopy Unit Confocal Microscopy Unit

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

Chart flow of the study Limitations of the study The study presents two possible limitations. The first is that a patient might have a disease-causing mutation in a gene is not known at present. For this type of patient we consider an exome study in an additional project if the family structure allows it. The common perception today is that the exome contains 85% of the disease-causing mutations. The second limitation is that in mutations produced by pathological repetitions may not be detected due to limitations on the technique used. This is a pilot project to assess these limitations, and in those cases where no gene can be examined by this technique we will use PCR and fragment analysis or other techniques to complete the information.

Cost justification The project cost estimation includes an expense for the project expenditure necessary reagents for DNA extraction and sequencing of the genes involved in ataxia.

Experimental design-workflow for PGM sequencer (Ion Torrent)

- Expected coverage in the experiment and type of chip used: Intended sequence in 48 patients, the coding region of 85 genes related recessive ataxia (62 genes) and dominant ataxias (23 genes). 1,327 sequencing include regions corresponding approximately 289 Kb of sequence per sample. Haloplex kit with total sequence amplicons would be 25,359 and the region of 715 kb would be the sequence size per sample with a coverage of 99.85%. At the same time, it aims to sequence the mitochondrial DNA of these same 48 patients. Sequencing includes the 16 Kb in size of mitochondrial DNA per sample.

Considering the total cost of the project, each patient studied include sequencing of all candidate genes for ataxia and sequencing of their mitochondrial DNA (Tables 1 and 2) would cost about 779 euros, and in the following cases this price would be lower as it includes the costs involved to develop a technique.

Once this technique is tuned it can be used to study any patient with genetic ataxias with a very affordable cost per test and overall giving the results in a few days.

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

References

1. Klockgether T, H Paulson. Milestones in ataxia Mov Disord. 2011 May; 26(6): 1134 -1141.

2. de Bot ST, et al. Reviewing the genetic causes of spastic-ataxias. Neurology. 2012 Oct 2;79(14):1507-14

3. Hersheson J, Haworth A, Houlden H. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat. 2012 Sep;33(9):1324-32.

4. Sailer A, et al. Recent advances in the genetics of cerebellar ataxias. Curr Neurol Neurosci Rep. 2012 Jun;12(3):227-36

5. Matilla-Dueñas A, Corral-Juan M, Volpini V, Sanchez I. The spinocerebellar ataxias: clinical aspects and molecular genetics. Adv Exp Med Biol. 2012;724:351-74.

6. Anheim M, et al. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012 Feb 16;366(7):636-46.

7. Verbeek DS, van de Warrenburg BP. Genetics of the dominant ataxias. Semin Neurol. 2011 Nov;31(5):461-9.

8. van Gaalen J, van de Warrenburg BP. A practical approach to late-onset cerebellar ataxia:

putting the disorder with lack of order into order. Pract Neurol. 2012 Feb;12(1):14-24.

9. Vermeer S, van de Warrenburg BP, Willemsen MA, Cluitmans M, Scheffer H, Kremer BP, Knoers NV. Autosomal recessive cerebellar ataxias: the current state of affairs. J Med Genet.

2011 Oct;48(10):651-9.

10. Kerber KA, S et al. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. J Neurol Sci 2005: 238: 41 -45.

11. Abele M, Burk K, Schols L et al. The aetiology of sporadic adult-onset ataxia. Brain 2002:

125: 961 -968.

12. Schöls L,et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet 2000: 107: 132 -137.

13. Jiménez-Escrig A, Gobernado I, Sánchez-Herranz A. [Whole genome sequencing: a qualitative leap forward in genetic studies]. Rev Neurol. 2012 Jun 1;54(11):692-8.

14. Jiménez-Escrig A, et al. Autosomal recessive Emery-Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing. Muscle Nerve. 2012 Apr;45(4):605-10.

15. Arnoult D, Soares F, Tattoli I, Girardin SE. Mitochondria in innate immunity. EMBO Rep 2011;12(9):901-10.

16. Tait SW, Green DR. Mitochondria and cell signalling. J Cell Sci 2012;125(Pt 4):807-15.

17. Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007;8(5):405-13.

18. Tschopp J. Mitochondria: Sovereign of inflammation? Eur J Immunol 2011;41(5):1196-202.

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

19. Jabaut J, et al. Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent ILbeta secretion in association with alterations in cellular redox and energy status. Free Radic Biol Med 2013;60:233-45.

20. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009;27:229-65.

21. Lee MS. Role of innate immunity in diabetes and metabolism: recent progress in the study of inflammasomes. Immune Netw 2011;11(2):95-9.22.

22. Keeley EC et al. Elevated circulating fibrocyte levels in patients with hypertensive...J.

Hypertens, 2012, 30: 1856-1861.

23. Németh AH, Kwasniewska AC, Lise S, Parolin Schnekenberg R, et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain.

2013 Oct;136(Pt 10):3106-18. doi: 10.1093/brain/awt236. Epub 2013 Sep 11.



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