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Heather Durham seeks to understand the mechanisms responsible for motor neuron diseases and to identify therapies to assist the vulnerable cells in defending themselves. Several genetic mutations responsible for familial forms of motor neuron diseases have been identified, which facilitates the establishment of cell culture and animal models to study in the laboratory. A common property of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), is an increased propensity of certain proteins to misfold, causing them to stick together, to associate with inappropriate partners, and to form insoluble aggregates in cells. These abnormalities occur in familial ALS because of genetic mutation, but also are generated through damage inflicted by the cellular environment in sporadic ALS.
To study why misfolded proteins accumulate and upset the physiology of the cells most vulnerable to damage, Durham has created primary culture models by expressing mutant genes linked to inherited forms of the disease in motor neurons of mouse spinal cord cultures. Focus has been on ALS due to mutations in SOD1 and in RNA binding proteins (FUS, TDP-43). Using these cultures and transgenic mouse models, her research is linking the vulnerability of motor neurons to the way in which they respond to stress and deal with damaged proteins. Recently, the lab has identified changes in chromatin remodeling in multiple forms of ALS including sporadic disease. They are testing two approaches for intervention: Histone deacetylase inhibitors to restore chromatin function and inducers of heat shock proteins that act as molecular chaperones to handle misfolded proteins. The combination of these drugs also is being tested to determine if they act synergistically. In culture models, advanced imaging methods are used to monitor biomarkers of disease progression. Findings in culture are then validated using complementary transgenic mouse models.
To study why misfolded proteins accumulate and upset the physiology of the cells most vulnerable to damage, Durham has created primary culture models by expressing mutant genes linked to inherited forms of the disease in motor neurons of mouse spinal cord cultures. Focus has been on ALS due to mutations in SOD1 and in RNA binding proteins (FUS, TDP-43). Using these cultures and transgenic mouse models, her research is linking the vulnerability of motor neurons to the way in which they respond to stress and deal with damaged proteins. Recently, the lab has identified changes in chromatin remodeling in multiple forms of ALS including sporadic disease. They are testing two approaches for intervention: Histone deacetylase inhibitors to restore chromatin function and inducers of heat shock proteins that act as molecular chaperones to handle misfolded proteins. The combination of these drugs also is being tested to determine if they act synergistically. In culture models, advanced imaging methods are used to monitor biomarkers of disease progression. Findings in culture are then validated using complementary transgenic mouse models.
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Mario Fernández Comaduran,Sandra Minotti,Suleima Jacob-Tomas, Javeria Rizwan, Nancy Larochelle,Richard Robitaille,Chantelle F. Sephton,M. Vera,Josephine N. Nalbantoglu,Heather D. Durham
Cell Stress and Chaperones (2024)
Celia Alecki, Javeria Rizwan,Phuong Le,Suleima Jacob-Tomas, Jia Stella M Xu,Sandra Minotti, Tad Wu,Heather Durham,Gene W Yeo,Maria Vera
bioRxiv : the preprint server for biology (2023)
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Maria Vera Ugalde,Célia Alecki, Javeria Rizwan, Phuong Le,Suleima Jacob-Tomas, Jia Ming Xu,Sandra Minotti, Tad Wu,Heather Durham,Gene Yeo
Research square (2023)
Afrooz Dabbaghizadeh, Alexandre Paré, Zacharie Cheng-Boivin,Robin Dagher,Sandra Minotti,Marie-Josée Dicaire,Bernard Brais,Jason C Young,Heather D Durham,Benoit J Gentil
Afrooz Dabbaghizadeh, Alexandre Paré, Zacharie Cheng-Boivin, Robin Dagher,Sandra Minotti,Marie-Josée Dicaire,Brais Bernard,Jason C. Young,Heather D. Durham,Benoit J. Gentil
bioRxiv (2021)
biorxiv(2020)
Rachel Kuta, Nancy Larochelle, Mario Fernandez,Arun Pal,Sandra Minotti,Michael Tibshirani, Kyle St. Louis,Benoit J. Gentil,Josephine N. Nalbantoglu,Andreas Hermann,Heather D. Durham
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