Understanding the molecular and cellular basis of neuropsychiatric disorders is one of the biggest and most significant challenges for the 21st century in neuroscience. Attention deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder and is characterized by inattention, distractibility, impulsivity, and/or the presence of hyperactivity. Numerous laboratories have shown that ADHD is highly heritable (approximate heritability is 0.8) although environmental factors also importantly influence its pathogenesis. To further advance our understanding of ADHD's molecular pathogenesis it is desirable to establish multipotent stem cells with the genetic backgrounds of ADHD and healthy subjects for biological and molecular comparisons. In 2006, Shinya Yamanaka and his colleagues published their groundbreaking work showing that pluripotent stem cells, so called "induced pluripotent stem (iPS) cells, can be generated from somatic cells by retroviral transduction of four transcription factors (i.e., Oct4, Sox2, Klf4 and c-Myc). Strikingly, several groups, including Yamamaka's, soon demonstrated that human iPS cells could be generated by similar methods. Although this iPS technology is still at an early stage and needs further development, based on these pioneering studies and our own preliminary results, we hypothesize that potential pathogenic mechanisms of ADHD can be investigated by generating ADHD-specific iPS cells and by using in vitro differentiation studies, comparing them with those of iPS cells derived from healthy subjects. Toward this long-term goal, during the R21 phase of the project, we propose (1) to establish multiple iPS lines from healthy and ADHD subjects, (2) to validate iPS cell lines by cellular, molecular, and differentiation analyses, and (3) to address whether the RAG1/RAG2 VDJ recombinase system can be used to screen and/or monitor human iPS cells'identity. In addition, during the R33 phase, we propose (1) to characterize the differentiation of individual iPS cell lines to expandable neural progenitors/precursors, (2) to characterize their differentiation to relevant neuronal subtypes such as dopaminergic and noradrenergic neurons, and (3) to compare cellular and differentiation properties of iPS cell lines from healthy and ADHD subjects for potential pathogenic mechanisms.

Public Health Relevance

Recent groundbreaking work by Shinya Yamanaka and his colleagues introduced the "induced pluripotent stem (iPS) cell" technology, a tantalizing new method generating genetically matched pluripotent stem cells without embryo destruction. To fully utilize this revolutionary technique, we propose to further advance this method by establishing a human iPS screening/monitoring system, and to generate and characterize multiple iPS lines from healthy and ADHD subjects. This approach will advance the iPS cell technology and provide a platform for investigating the biological and molecular mechanisms underlying ADHD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33MH087903-04
Application #
8324016
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Panchision, David M
Project Start
2009-09-30
Project End
2013-09-30
Budget Start
2012-07-01
Budget End
2013-09-30
Support Year
4
Fiscal Year
2012
Total Cost
$389,141
Indirect Cost
$142,849
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Park, Hansoo; Kim, Dohoon; Kim, Chun-Hyung et al. (2014) Increased genomic integrity of an improved protein-based mouse induced pluripotent stem cell method compared with current viral-induced strategies. Stem Cells Transl Med 3:599-609
Kim, Tae-Gon; Yao, Ruiqin; Monnell, Travis et al. (2014) Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation. Stem Cells 32:1789-804
Kim, Kyoung-Shim; Kang, Young-Mi; Kang, Young et al. (2014) Pitx3 deficient mice as a genetic animal model of co-morbid depressive disorder and parkinsonism. Brain Res 1552:72-81
Chung, Sangmi; Moon, Jisook; Kim, Kwang-Soo (2014) Improvement of neurological dysfunctions in aphakia mice, a model of Parkinson's disease, after transplantation of ES cell-derived dopaminergic neuronal precursors. Methods Mol Biol 1213:285-91
Moon, Jisook; Lee, Hyun-Seob; Kang, Jun Mo et al. (2013) Stem cell grafting improves both motor and cognitive impairments in a genetic model of Parkinson's disease, the aphakia (ak) mouse. Cell Transplant 22:1263-79
Park, Kyung-Soon; Cha, Young; Kim, Chun-Hyung et al. (2013) Transcription elongation factor Tcea3 regulates the pluripotent differentiation potential of mouse embryonic stem cells via the Lefty1-Nodal-Smad2 pathway. Stem Cells 31:282-92
Vasudevan, Anju; Won, Chungkil; Li, Suyan et al. (2012) Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain. Development 139:3136-41
Chung, Sangmi; Kim, Chun-Hyung; Kim, Kwang-Soo (2012) Lmx1a regulates dopamine transporter gene expression during ES cell differentiation and mouse embryonic development. J Neurochem 122:244-50
Hong, Seok Jong; Huh, Yang Hoon; Leung, Amanda et al. (2011) Transcription factor AP-2β regulates the neurotransmitter phenotype and maturation of chromaffin cells. Mol Cell Neurosci 46:245-51
Chung, Sangmi; Moon, Jung-Il; Leung, Amanda et al. (2011) ES cell-derived renewable and functional midbrain dopaminergic progenitors. Proc Natl Acad Sci U S A 108:9703-8

Showing the most recent 10 out of 16 publications