The broad, long-term objective of the project is to validate CaV1.3 voltage-gated calcium (Ca2+) channels and TRPC1 store-operated Ca2+ channels as novel therapeutic targets for treatment of Huntington's disease. Huntington's disease (HD) is an autosomal-dominant and fatal neurodegenerative disorder caused by polyglutamine repeat (polyQ) expansion in the amino-terminal of Huntingtin (Htt) protein. Striatal medium spiny neurons (MSN) are preferentially affected in HD. A number of toxic functions have been assigned to mutant Htt, but exact causes of HD pathology remain unknown and no disease-modifying therapy has been developed. Deranged Ca2+ signaling has been proposed to play a key role in HD pathogenesis. Voltage-gated (VGCCs) and store-operated (SOC) Ca2+ channels are important regulators of neuronal Ca2+ signaling, and recent evidence suggested potential importance of these channels in HD. I propose: 1. To develop the physiological in vitro assay for HD toxicity by establishing co-cultures from cortical and striatal neurons from YAC128 HD mice. 2. To validate the CaV1.3 L-type voltage-gated Ca2+ channel as potential target for HD treatment in vitro and in vivo using genetic methods. 3. To validate the TRPC1 store-operated Ca2+ channel as potential target for HD treatment in vitro and in vivo using genetic methods. 4. To evaluate pharmacological inhibitors of CaV1.3 VGCC and TRPC1-supported SOC channels as potential therapeutic agents for HD treatment in cell culture and whole animal experiments with YAC128 HD mouse model. Validation of CaV1.3 VGCC and TRPC1 SOC channels as novel therapeutic targets for HD will create an opportunity for developing novel therapeutic agents for cure of HD.

Public Health Relevance

The proposed project will have direct and immediate relevance for public health. Huntington's disease (HD) is an incurable genetic disorder that causes enormous suffering. The experiments described in the grant are aimed at validating novel therapeutic targets for treatment of HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074376-02
Application #
8448608
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (92))
Program Officer
Sutherland, Margaret L
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$335,639
Indirect Cost
$124,545
Name
University of Texas Sw Medical Center Dallas
Department
Physiology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ryskamp, Daniel; Wu, Jun; Geva, Michal et al. (2017) The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis 97:46-59
Zhemkov, Vladimir A; Kulminskaya, Anna A; Bezprozvanny, Ilya B et al. (2016) The 2.2-Angstrom resolution crystal structure of the carboxy-terminal region of ataxin-3. FEBS Open Bio 6:168-78
Wu, Jun; Ryskamp, Daniel A; Liang, Xia et al. (2016) Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model. J Neurosci 36:125-41
Egorova, Polina; Popugaeva, Elena; Bezprozvanny, Ilya (2015) Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease. Semin Cell Dev Biol 40:127-33
Fedorenko, Olena A; Popugaeva, Elena; Enomoto, Masahiro et al. (2014) Intracellular calcium channels: inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39-48
Poguzhelskaya, Ekaterina; Artamonov, Dmitry; Bolshakova, Anastasia et al. (2014) Simplified method to perform CLARITY imaging. Mol Neurodegener 9:19
Kim, Meewhi (2014) Pathogenic polyglutamine expansion length correlates with polarity of the flanking sequences. Mol Neurodegener 9:45
Liang, Xia; Wu, Jun; Egorova, Polina et al. (2014) An automated and quantitative method to evaluate progression of striatal pathology in Huntington's disease transgenic mice. J Huntingtons Dis 3:343-350
Bezprozvanny, Ilya (2013) Reconstitution of endoplasmic reticulum InsP3 receptors into black lipid membranes. Cold Spring Harb Protoc 2013:
Bezprozvanny, Ilya (2013) Bilayer measurement of endoplasmic reticulum Ca2+ channels. Cold Spring Harb Protoc 2013:

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