Research in the Davidson Laboratory

Dr. Davidson:
Research in my laboratory is focused on inherited genetic diseases that cause central nervous system dysfunction, with a focus on (1) recessive, childhood onset neurodegenerative disease, in particular the lysosomal storage diseases such as the mucopolysaccharidoses and Battens disease; and (2) dominant genetic diseases for example the CAG repeat disorders, Huntington’s disease and spinal cerebellar ataxia type I, and (3), understanding how noncoding RNAs participate in neural development and neurodegenerative diseases processes.

Our research on childhood onset neurodegenerative diseases is focused on experiments to better understand the biochemistry and cell biology of proteins deficient in these disorders, and to develop gene small molecule based medicines for therapy. In recent work we demonstrated that the application of recombinant viral vectors to animal models of storage disease reversed CNS deficits.

Therapies for dominant disorders are an exciting challenge and require that the dominant disease allele be silenced. To approach this, we developed reagents for expressing inhibitory RNA in vivo. This approach improved disease phenotypes in relevant models of dominantly inherited human neurodegenerative diseases.

Finally, we investigate how naturally occurring noncoding RNAs, miRNAs, participate in cell fate decisions in normal development, and how their expression is altered in disease states. We find that miRNAs with altered expression in Huntington’s disease or spinocerebellar ataxia brains target proteins that themselves contribute to disease phenotypes. This work may reveal new targets for drug therapy.

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1. Eliason SL, Stein CS, Mao Q, Tecedor L, Ding SL, Gaines DM, Davidson BL. A knock-in reporter model of Batten disease. J Neurosci. 27(37):9826-34, 2007. (Abstract)

2. Mao Q, Xia H, Davidson BL. Intracellular trafficking of CLN3, the protein underlying the childhood neurodegenerative disease, Batten disease. FEBS Lett 555:351-357, 2003. (Abstract)

3. Liu G, Martins I, Wemmie JA, Chiorini JA, Davidson BL. Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus. J Neurosci 25(41):9321-9327, 2005. (Abstract)

4. Liu G, Chiorini J, Heth J, Martins I, Chen YH, Davidson BL. AAV5 mediated functional correction in the mouse CNS of MPS mice. Mol Ther 15(2):242-7, 2007. (Abstract)

5. Davidson, BL, Boudreau RL. RNA interference: a tool for querying nervous system function and an emerging therapy. Neuron 53(6):781-8. 2007. (Abstract)

6. Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL, Davidson BL. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. PNAS 102(16):5820-5825, 2005. (Abstract)

7. Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, Paulson HL, Yang L, Kotin RM, Davidson BL. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10(8):816-820, 2004. (Abstract)

8. Kumar P, Wu H, McBride JL, Jung KE, Hee Kim M, Davidson BL, Kyung Lee S, Shankar P, Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature PMID 17572664, 2007. (Abstract)

9. Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13(12):1097-1101, 2006 - Article of the month. (Abstract)