Maryamsadat Hashemi has been born in Iran 12 May 1987. She received bachelor education in Applied mathematics Science at University of Shahrerey, in 2010. In 2018 she received a master degree in Pharmacy at University of Turin, Italy. During her thesis she studied, L-type calcium channel gating defects induced by CACNA1D mutation associated with autistic spectrum disorder. She started her PhD course in Experimental Neuroscience at the University of Milano-Bicocca (Monza, Italy). Her PhD research project involves the investigation neurotoxicity of antineoplastic agents and possible role of MAP1B-LC1 protein complex in Cav3.2 channel trafficking.
PROGETTO DI RICERCA
Curriculum: Neuroscienze sperimentali
Tutor: Dott.ssa Gabriella Nicolini
Studies have been shown that LC1 of MAP1B interacts with the Cav2.2 channels and favors their ubiquitination. We hypothesized MAP1B-LC1 protein complex could have a very important role in the trafficking of Cav3.2 channel which is expressed in sensory neurons and is responsible for 80% of the T type calcium . Cav 3.2 is considered the most important molecule involved in neuropathic pain. Following treatment with bortezomib and paclitaxel the calcium current increases and could relate to the alterations of the microtubules. The aim of this project will be to investigate bortezomib and paclitaxel neurotoxicity in primary cultures of mouse dorsal root ganglia mouse focusing on the possible correlation between the MAP1B-LC1 complex and the Cav3.2 channel trafficking.
Peripheral neuropathy is a principal dose-limiting factor for each of the major frontline chemotherapeutics used against all the most common cancers and thus effects thousands of patients each year. Peripheral neuropathy can force dose reduction or even discontinuation of therapy, however, the mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN) and potential molecular targets for pharmacotherapy are stile poorly understood. Accumulating evidence from preclinical studies employing rodent models for CIPN caused by some anticancer agents, such as oxaliplatin and paclitaxel, bortezomib suggests, the involvement of multiple mechanisms in the pathophysiology of CIPN ex: mitochondrial dysfunction, oxidative stress, altered expression and/or function of ion channel:(like voltage gated Ca 2+ channels) and changes in cytoskeleton. It is very interesting to know that paclitaxel and bortezomib, belonging to two different families of antineoplastic agents, cause both alteration of the microtubules.
Microtubules (MTs) are an array of α and β-tubulin heterodimers stuck together in a head-to-tail fashion, which laterally from a rather stiff, hollow tubular structure of about 25 nm diameter.
In neurons, bundles of MTs are kept together and stabilized by structural microtubule-associated proteins (MAP) crosslinks. There are numerous identified MAPs that have been divided into type 1 including MAP1 proteins and type 2 including MAP2, MAP4 and tau proteins. MAP1A and MAP1B are predominantly expressed in neurons where they are thought to be important in the formation and development of axons and dendrites. The MAP1A andMap1B are translated as large proteins that are processed by proteolytic cleavage near the C-terminal region leading to the generation of heavy chains and light chains, LC1 and LC2.
- In vitro model: Primary cultures of neurons from dorsal root ganglia of adult male C 57BL/6JOlaHsd 8 weeks mouse.
- Whole-cell patch clamp technique to measure the current of the Cav3.2 channel
- Western blotting and immunoprecipitation experiments to evaluate the expression levels of various proteins such as MAP1B, phospho MAP1B and Cav3.2 and the possible interaction between proteins (for example MAP1b and EB1-3).
- Immunofluorescence and confocal microscopy to study the distribution of the proteins under investigation and to characterize microtubule organization and distribution.
- Guarina L., Hofer N, Hashemi M. S., Marcantoni A.,Ortner N.J., Carbone E., Striessnig J., “Altered firing and L-type channel gating in the adrenal chromaffin cells of a mouse model(CavAG) carrying an autism-associated de novo CACNA1D point mutation of Cav1.3 calcium channels”- March 15, 2018