Project Details
Abstract
Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by a CAG
trinucleotide repeat expansion in the huntingtin gene, which results in a protein with an abnormally long
polyglutamine sequence. As the disease progresses, patients gradual worsen in controlling their movements,
cognitive decline, and psychiatric symptoms. Despite several symptoms-ameliorative treatment options, there
is currently no cure or treatment to slow the progression of the disease. Our previous studies have shown that
focused ultrasound (FUS) sonicating in the presence of microbubbles (MBs) with glia cell line-derived
neurotrophic factor (GDNF) can potentially and locally enhancing GDNF overexpression in striatum of HD
transgenic mice for disease modification or treatment. In this research project, we will continue to develop
molecular imaging-guided focused ultrasound (FUS) system to precisely and noninvasively focus the
ultrasound beam at the desired region to disrupt the local BBB in HD transgenic mice.
Our previous studies also indicate that MB dose, sonication duration, acoustic pressure are the major factors
affecting the HD-BBB opening and the side effects with ages. In addition to the amount of therapeutic agents
delivered into the desired location, safety is another major challenge for FUS-induced HD-BBB opening. To
establish a safe operation procedure, we will use a real-time image guiding and monitoring system to handle
the BBB disruption in order to enhance the vascular permeability with minimum side effects on the tissues.
HD transgenic mouse model with different ages will be used in this study and we will use the model to
evaluate the system ability of safe delivery for therapeutic reporter genes brain-derived neurotrophic factor
(BDNF) plasmid DNA into the desired treatment region. Then, BDNF overexpression can lead the protective
effect in the growth, maturation, and maintenance for corticobasal neural circuit. This novel therapeutic
technique with image-guidance and monitoring can also be applied to other rarely neurodegenerative
diseases. The major jobs in this research project are listed as following:
1. Development of noninvasive molecular imaging-guided FUS system for theranostic hereditary
neurodegenerative disease;
2. Investigation for the safety of HD-BBB opening with different ages and for image-guided FUS system;
3. Investigation of BDNF gene expression and therapeutic efficacy in aged HD transgenic mice for
image-guided FUS system.
4. Investigation of BDNF gene expression for stimulating CNS neuronal maturation, survival and neural
plasticity factors in HD-BBB opened tissues.
This is a three-year research project. For the first year (2017/8-2018/7), we will evaluate the optimal
parameters for FUS systems enhancing BDNF expression and safety with molecular image-guided systems
and to demonstrate the capability of the designed system capable of targeted opening the BBB in aged HD
transgenic mice, and successfully inducing gene transduction into targeted tissues. For the second year
(2018/8-2019/7), the major jobs are evaluating the image-guided FUS system for HD-BBB opening and
studying the therapeutic efficacy of BDNF delivery. For the third year (2019/8-2020/7), to investigate the
downstream pathways of BDNF overexpression, including p-CREB/CREB, p-AKT/AKT, p-BAD/BAD,
p-BCL2/BCL2 and caspase-3 expression.
Project IDs
Project ID:PB10612-0037
External Project ID:MOST106-2221-E182-080
External Project ID:MOST106-2221-E182-080
Status | Finished |
---|---|
Effective start/end date | 01/08/17 → 31/07/18 |
Keywords
- Huntington’s disease
- focused ultrasound in therapeutics
- Brain-derived neurotrophic factor
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