البيانات الاساسيه

السيره الذاتيه

السيرة الذاتية لدكتورة رشا حسين

أولاً : البيانات الشخصية

ثانيا: المؤهلات العلمية

ثالثا: الإنتاج العلمي

أ. الرسائل العلمية 

الدوريات

عنوان رسالة الماجستير

In vitro combinatorial therapeutics in breast cancer against the Notch and PI3K pathways

ملخص رسالة الماجستير

Purpose: Several studies indicate that T- acute lymphoblastic leukemia (T-ALL) cell lines that exhibit activation of both Notch andphosphoinositidine 3-Kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) are resistant to gamma secretase inhibitor (GSI) treatment. In this study, we investigated the sensitivity and /or resistance of breast cancer cell lines to the inhibition of Notch pathway by gamma secretase inhibitor (DBZ) and inhibition of PI3K/AKT/mTOR inhibitor ( rapamycin) both alone or in combination . Methods: Six breast cancer cell lines with down regulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and overexpressed Notch homologs were identified and treated with DBZ and rapamycin alone or in combination for ten days. The inhibition of cell proliferation was evaluated by alamar blue assay and efficiency of pathway inhibition was assessed by Western blot of Notch 1, Notch 3 and phospho-p70 S6K target proteins. Results: Our breast cancer cell lines showed variable sensitivity to rapamycin treatment and generally were resistant to DBZ treatment. However, the combinatorial treatment was highly effective for all but one cell line and could significantly reduce cell proliferation and growth compared to each drug alone (p< 0.001). Conclusion: The combinatorial treatment of DBZ and rapamycin provides a promising therapeutic option for GSI-resistant breast cancers.

عنوان رسالة الدكتوراه

The specific role of small heat shock proteins as chaperone in protecting against protein aggregation mediated diseases

ملخص رسالة الدكتوراه

The molecular chaperones play an important role in the protein quality control in cells as they maintain the proteostasis and protect cells from the harmful aggregates associated with numerous diseases such as Alzheimer’s disease. Throughout this thesis, we investigated the effect of DNAJB6 chaperone on the aggregation of Aβ42 peptides associated with Alzheimer’s disease both in vitro and in cultured cells. In addition, we studied a case of HSPB5 chaperonopathy and demonstrated the specific domains involved in the interaction between HSP21 chaperone and its substrate protein, malate dehydrogenase. We found that DNAJB6 chaperone effectively prevents the aggregation of Aβ42 peptides at sub-stochiometric molar ratios through binding to various Aβ oligomeric species rather than binding to Aβ monomers. Thus, DNAJB6 inhibits the primary and secondary nucleation pathways of Aβ fibrillation process. Moreover, we investigated the effect of DNAJB6 on the aggregation of Aβ-GFP fusion protein in mammalian cells and we found that DNAJB6 also prevents the aggregation of Aβ-GFP through a canonical J-domain dependence. Parallel to our in vitro results, DNAJB6 could not prevent the aggregation of the preformed Aβ fibrils that are exogenously applied to cells. Moreover, we observed that Aβ-GFP model may not reflect the same characteristics of Aβ peptides mediated aggregation. In addition, we studied a case of HSPB5 chaperonopathy in which HSPB5 is genetically mutated and causes cataract, myopathy diseases and associated with formation of intracellular aggregates. We systematically screened the effect of overexpression of HSPB (1-10) in an attempt to find out candidates that can rescue the aggregation of HSPB5 mutants. We found that only the hetero-oligomeric partners, which normally interact with HSPB5, are able to reduce the aggregation of HSPB5 mutants. This protective effect was not attributed to increase in refolding by HSP70 nor increase in the degradation rate of the mutant protein. Therefore, this protective effect may suggest for a compensating mechanism mediated by the hetero-oligomeric partners. Interestingly, the non-mammalian HSP21 chaperone showed a protective effect against the aggregation of the thermo sensitive malate dehydrogenase (MDH) substrate. Crosslinking the transient interaction and the formed complex between HSP21 and MDH followed by mass spectrometry revealed that HSP21 chaperone interacts through its N-terminal domain with the C- terminal domain of MDH to prevent the aggregation.