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My laboratory is interested in using the mouse molecular genetic approach to study the pathogenesis of neurodegenerative diseases. One recurring theme in neurodegenerative diseases is that a widely expressed mutant protein can cause highly selective degeneration of a subset of neurons. The pathogenesis of such selective neurodegeneration remains unclear. Currently, we are focusing on Huntington’s disease (HD) to study the molecular and cellular mechanisms underlying the selective degeneration of the striatal and cortical neurons in the disease. It remains unclear whether the selective neurodegeneration in HD is primarily due to toxicities of mutant Huntingtin (Ht) within the vulnerable neurons (the suicide model) or secondary to dysfunction or degeneration of other neurons or glia (the murder model), or due to both toxicities (assisted suicide model). To address this question, we have developed two conditional mouse models of HD. In the first model, expression of mutant Ht exon1 can be activated by Cre-mediated recombination. By using different mouse Cre lines, we have developed an allelic series of HD mouse models with mHt expression is activated in the cortical neurons only, striatal neurons only, or throughout the entire CNS. These models will allow us to understand whether cell-autonomous or non-cell autonomous toxicites of mHt is required for the dysfunction and degneration of the most vulnerable cortical and striatal neurons. In addition to the conditional activation model, we have also generated a full length conditional inactivation model of HD using Bacterial Artificial Chromosome (BAC)- mediated transgenesis. BACs are large cloned genomic DNA (average size 180-200kb) and our previous work has demonstrated that BAC transgenes can consistently confer high level, and endogenous-like gene expression in vivo. In this BAC transgenic model of HD, full length mutant Ht expression can be conditionally inactivated by Cre-mediated recombination. Using these two conditional HD models, we are particularly interested in addressing the hypothesis that non-cell autonomous toxicities of mHt is necessary and perhaps sufficient to cause selective degeneration of striatal and cortical neurons in HD. Another research interest in my laboratory is to applly the BAC modification and BAC transgenic technology to develop mouse models for Parkinson’s disease (PD). Currently we are using the BACs to overexpress PD-related mutant proteins in the mouse brain. In the long run, my laboratory will use these novel mouse model systems to systematically study key pathogenic mechanisms and to test therapeutic strategies for these devastating neurodegenerative diseases.
My laboratory is interested in using the mouse molecular genetic approach to study the pathogenesis of neurodegenerative diseases. One recurring theme in neurodegenerative diseases is that a widely expressed mutant protein can cause highly selective degeneration of a subset of neurons. The pathogenesis of such selective neurodegeneration remains unclear. Currently, we are focusing on Huntington’s disease (HD) to study the molecular and cellular mechanisms underlying the selective degeneration of the striatal and cortical neurons in the disease. It remains unclear whether the selective neurodegeneration in HD is primarily due to toxicities of mutant Huntingtin (Ht) within the vulnerable neurons (the suicide model) or secondary to dysfunction or degeneration of other neurons or glia (the murder model), or due to both toxicities (assisted suicide model). To address this question, we have developed two conditional mouse models of HD. In the first model, expression of mutant Ht exon1 can be activated by Cre-mediated recombination. By using different mouse Cre lines, we have developed an allelic series of HD mouse models with mHt expression is activated in the cortical neurons only, striatal neurons only, or throughout the entire CNS. These models will allow us to understand whether cell-autonomous or non-cell autonomous toxicites of mHt is required for the dysfunction and degneration of the most vulnerable cortical and striatal neurons. In addition to the conditional activation model, we have also generated a full length conditional inactivation model of HD using Bacterial Artificial Chromosome (BAC)- mediated transgenesis. BACs are large cloned genomic DNA (average size 180-200kb) and our previous work has demonstrated that BAC transgenes can consistently confer high level, and endogenous-like gene expression in vivo. In this BAC transgenic model of HD, full length mutant Ht expression can be conditionally inactivated by Cre-mediated recombination. Using these two conditional HD models, we are particularly interested in addressing the hypothesis that non-cell autonomous toxicities of mHt is necessary and perhaps sufficient to cause selective degeneration of striatal and cortical neurons in HD. Another research interest in my laboratory is to applly the BAC modification and BAC transgenic technology to develop mouse models for Parkinson’s disease (PD). Currently we are using the BACs to overexpress PD-related mutant proteins in the mouse brain. In the long run, my laboratory will use these novel mouse model systems to systematically study key pathogenic mechanisms and to test therapeutic strategies for these devastating neurodegenerative diseases.
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Natureno. 7995 (2024): E16-E16
Juhyuk Park,Ji Wang,Webster Guan,Lars A. Gjesteby, Dylan Pollack,Lee Kamentsky,Nicholas B. Evans, Jeffrey Stirman, Xinyi Gu, Chuanxi Zhao, Slayton Marx,Minyoung E. Kim,
biorxiv(2024)
C Y Daniel Lee, Amberlene J De La Rocha, Kellie Inouye,Peter Langfelder,Anthony Daggett,Xiaofeng Gu,Lu-Lin Jiang,Zoe Pamonag,Raymond G Vaca,Jeffrey Richman,Riki Kawaguchi,Fuying Gao,
bioRxiv : the preprint server for biology (2023)
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Daniel K. Wilton,Kevin Mastro, Molly D. Heller, Frederick W. Gergits,Carly Rose Willing, Jaclyn B. Fahey,Arnaud Frouin,Anthony Daggett,Xiaofeng Gu, Yejin A. Kim,Richard L. M. Faull,Suman Jayadev,
Nature Medicineno. 11 (2023): 2866-2884
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Daniel O'Reilly,Jillian Belgrad,Chantal Ferguson,Ashley Summers,Ellen Sapp, Cassandra McHugh, Ella Mathews,Adel Boudi,Julianna Buchwald,Socheata Ly,Dimas Moreno,Raymond Furgal,
C.Y. Daniel Lee, Ademir Rocha, Ken Inouye,Peter Langfelder,Anthony Daggett,Xiaofeng Gu,LuLin Jiang,Zoe Pamonag,Raymond G Vaca,Jeffrey Richman,Riki Kawaguchi,Fuying Gao,
bioRxiv (Cold Spring Harbor Laboratory) (2023)
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