Duke Department of Medicine, Division of Neurology
Bryan Alzheimer's Disease Research Center and
Duke Institute for Genome Sciences & Policy
Duke University Medical Center
Durham, NC 27710
905 S. LaSalle Street
GSRB I, Room 2005
Durham, NC 27710
Our research interests center around the genetics of complex neurological diseases. Specifically, we focus on two major areas:
1. The significance and functional consequences of genomic regions/genes associated with neurodegenerative-diseases
Our work capitalizes on the identification of genomic regions and/or genes as highly significant genetic risk factors through candidate-genes and genome-wide based association studies.
Our goal is to reveal the mechanism by which the associated regions contribute to disease susceptibility. Pinpointing the causal genetic variants within a genomic region that has been implicated in disease by association studies is a current, though a challenging need.
First, this is due to the fact that most genetic variants were implicated due to linkage disequilibrium with the causal variant, which only occasionally was directly called. Moreover, many identified associations map to non-coding regions. Thus for the majority of the complex disease associated genomic region the precise causal variant remains unknown. Primarily we test the hypothesis that changes in expression levels of normal protein can lead to neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases.
Using post-mortem human brain tissues, cell-based systems and humanized mouse model we have been studying the effect of genetic variations within a genomic region of interest on gene expression pattern.
In particular we investigate three model genes: SNCA, implicated in Parkinson’s disease; TOMM40 and SORL1 involved in Alzheimer’s disease. By determining the functional association of genetic variants with differential expression we advance the identification of novel causal variants and hence impact our understanding of the genetic factors and molecular mechanisms underlying common neurodegenerative disorders
The lab is also member of both the Bryan Alzheimer’s Disease Research Center (ADRC) and the Duke University’s Institute for Genome Sciences & Policy that provides the foundation for the establishment of this unique collaborative program between these two centers at Duke.
Using a comprehensive battery of the different neuropsychiatric tests we are currently developing endophenotypes to establish a thorough phenotypic characterization of mild cognitive impairment (MCI) vs. normal controls. In addition we have initiated fine phenotypic characterization to identify individuals over the age of 85 who we define as successful cognitive aging. These cognitive endophenotypes will be used in genetic tests by candidate genes and whole genome approaches to investigate the genetics basis of cognitive changes in elderly.
The Chiba-Falek lab is working very closely with the Deane Drug Discovery Laboratory headed by Dr. Allen Roses.
1. Rave-Harel N, Madgar I, Goshen R, Nissim-Rafinia M, Ziadni A, Rahat A, Chiba O, Kalman YM, Brautbar C, Levinson D, Augarten A, Kerem E and Kerem B. (1995) CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens. Am J Hum Genet 56:1359-1366.
2. Kerem B, Chiba-Falek O and Kerem E. (1997) Cystic fibrosis in Jews: frequency and mutation distribution. Genetic Testing 1:35-39.
3. Kerem E, Rave-Harel N, Augarten A, Madgar I, Nissim-Rafinia M, Yahav Y, Goshen R, Bentur L, Rivlin J, Aviram M, Genem A, Chiba-Falek O, Kraemer MR, Simon A, Branski D and Kerem B. (1997) A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations. Am J Respir Crit Care Med 155:1914-1920.
4. Kerem E, Nissim-Rafinia M, Argaman Z, Augarten A, Bentur L, Klar A, Yahav Y, Szeinberg A, Chiba-Falek O, Branski D, Corey M and Kerem B. (1997) A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics 100:1-6.
5. Chiba-Falek O, Nissim-Rafinia M, Argaman Z, Genem A, Moran I, Kerem E and Kerem B. (1998) Screening of CFTR mutations in an isolated population: identification of carriers and patients. Eur J Hum Genet 6:181-184.
6. Chiba-Falek O, Kerem E, Shoshani T, Aviram M, Augarten A, Bentur L, Tal A, Tullis E, Rahat A and Kerem B. (1998) The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10kb C->T mutation. Genomics 53:276-283.
7. Chiba-Falek O, Parad RB, Kerem E and Kerem B. (1999) Variable levels of normal RNA in different fetal organs carrying a CFTR splicing mutation. Am J Respir Crit Care Med 159:1998-2002.
8. Nissim-Rafinia M*,Chiba-Falek O*, Sharon G, Boss A, and Kerem B. (2000) Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations. Hum Mol Genet 9:1771-1778.
* Equal contribution.
9. Touchman JW, Dehejia A, Chiba-Falek O, Cabin DE, Schwartz JR, Orrison BM, Polymeropoulos MH and Nussbaum RL. (2001) Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. Genome Res 11:78-86. PMCID: PMC311023
10. Chiba-Falek O and Nussbaum RL. (2001) Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10:3101-9.
11. Chiba-Falek O, Touchman JW and Nussbaum RL. (2003) Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. Hum Genet 113:426-431.
12. Chiba-Falek O and Nussbaum RL. (2003) Regulation of alpha-synuclein expression: implications for Parkinson's disease. Cold Spring Harb Symp Quant Biol 68:409-415.
13. Nissim-Rafinia M, Aviram M, Randell SH, Shushi L, Ozeri E, Chiba-Falek O, Eidelman O, Pollard HB, Yankaskas JR and Kerem B. (2004) Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation. EMBO Rep. 5:1071-1077.
14. Chiba-Falek O, Kowalak JA, Smulson ME and Nussbaum RL. (2005) Regulation of a-synuclein expression by Poly (ADP ribose)polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. AJHG 76:478-492. PMCID: PMC1196399
15. Chiba-Falek O, Lopez GJ and Nussbaum RL. (2006) Levels of Alpha-synuclein (SNCA) mRNA in sporadic Parkinson disease patients. Movement Disorders 21:1703-1708.
16. Cronin KD, Ge D, Manninger P, Linnertz C, Rossoshek A, Orrison BM, Bernard DJ, El-Agnaf OMA, Schlossmacher MG, Nussbaum RL and Chiba-Falek O. (2009) Expansion of the Parkinson disease-associated SNCA-Rep1 allele up-regulates human a-synuclein in transgenic mouse brain. Hum Mol Genet 18:3274-85. PMCID: PMC2722989
17. Linnertz C, Saucier L, Ge D, Cronin K D, Burke JR, Browndyke JN, Hulette CM, Welsh-Bohmer KA and Chiba-Falek O. (2009) Genetic regulation of a-synuclein mRNA expression in various human brain tissues. PLoS ONE 4(10): e7480. doi:10.1371/journal.pone.0007480. PMCID: PMC2822818
18. Heinzen EL, Need AC, Hayden KM, Chiba-Falek O, Roses AD, Strittmatter WJ, Burke JR, Hulette CM, Welsh-Bohmer KA and Goldstein DB. (2010) Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer's Disease. J Alzheimers Dis. PMCID: PMC2883723
19. Chiba-Falek O, Nichols M, Suchindran S, Guyton JR, Ginsburg GS, Barrett-Connor E and McCarthy JJ. (2010) Sex-specific effects of scavenger receptor class B type 1 (SR-BI) gene variants on serum lipid levels and hepatic gene expression. BMC Medical Genetics 11(1):9. PMCID: PMC2822818
20. McCarthy JJ, Linertz C, Saucier L, Burke JL, Hulette CM, Welsh-Bohmer KA and Chiba-Falel O. (2011) The Effect of SNCA 3' Region on the Levels of SNCA-112 Splicing Variant. Neurogenetics 12(1)59-64. PMCID: PMC3030669
21. Cirulli ET, Attix DK, Smith PJ, Chiba-Falek O, Pennuto TO, Linney KN, Goldstein DB. (2011) Contribution of Pastimes and Testing Strategies to the Performance of Healthy Volunteers on Cognitive Tests. Clin Neuropsychol 25(5):778-98.
22. McCarthy JJ, Saith S, Linnertz C, Burke JR, Hulette CM, Welsh-Bohmer KA and Chiba-Falek O. (2012) The Alzheimer's associated 5' region of the SORL1 gene cis-regulates SORL1 transcripts expression. Neurobiology of Aging 33(7):1485.e1-8. PMCID: PMC3117021
23. Linnertz C, Saunders AM, Lutz MW, Crenshaw DM, Grossman I, Burns DK, Whitfield KE, Hauser MA, McCarthy JJ, Ulmer M, Allingham R, Welsh-Bohmer KA, Roses AD and Chiba-Falek O. (2012) Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations. PLoS ONE 7(2):e30994. PMCID: PMC3281049
24. Hayden KM, McEvoy JM, Colton Linnertz C, Attix D, Kuchibhatla M, Saunders AM, Lutz MW, Welsh-Bohmer KA, Roses AD and Chiba-Falek O. (2012) A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging. Alzheimer's and Dementia [Epub ahead of print].
25. Browndyke JN, Giovanello K, Petrella J, Hatden K, Chiba-Falek O, Tucker KA, Burke JR, Welsh-Bohmer KA. (2012) Phenotypic regional functional imaging patterns during memory encoding in mild cognitive impairment and Alzheimer's disease. Alzheimer's and Dementia [Epub ahead of print].
26. Chiba-Falek O, Linnertz C, Guyton J, Gardner SD, Roses AD, McCarthy JJ, Patel K. (2012) Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection. HumGenet [Epub ahead of print].