Targeting TGF- b resistance in cancer using exosomes-mediated delivery of siRNA-based drugs
Project-I: Targeting TGF- b resistance in cancer using exosomes-mediated delivery of siRNA-based drugs
Transforming growth factor-β (TGF- β) is a superfamily of growth factors which regulate a wide range of cellular responses and have prominent role in tissue homeostasis and development. Aberrations in the TGF- β signaling pathway including deletion or mutation in any component of the signaling pathway consequently induces the resistance against cytostatic activity of TGF- β. This resistance is often associated with the human cancers. In cancer, TGF- β plays two conflicting roles as tumor promoter as well as tumor suppressor. TGF- β downregulates the expression of E-cadherin as well as induce the expression of invasion-associated proteins to induce Epithelial to mesenchymal transition (EMT). TGF- b induces the expression of matrix metalloproteases for the degradation of extracellular matrix (ECM) to facilitate the invasion of neighboring tissues by the cancer cells. TGF- b also aids the cancer cells to evade apoptosis by activating PI-3 kinase/Akt pathway. Targeting the TGF- b pathway to inhibit its tumor promoter attributes is an attractive strategy to control the cancer progression. However, the molecular basis for oncogenic properties of TGF-β are still unknown. One potential reason for TGF-β resistance in cancer cells can be lack of TGF-β activation. This lack of activation is evident by enhanced expression of latent TGF-β in several cancers might be due reduced expression of latent TGF-β activation proteins such FURIN and Thrombospondin-I (THBSI). p53 mutation, a key mutation in several cancers, also results in the decrease of Thrombospondin-I (THBSI) expression. The aim of this study is to explore the TGF- b resistance paradox by targeting the TGF-b using siRNA-based drug. This will provide an insight into factors which contribute to the resistance to TGF-b induced inhibition of tumor progression.
Project: II: Developing mRNA-based vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
Since the emergence of SARS-CoV-2 in China, this virus spread rapidly across the globe and declared as global pandemic in March 2020 by World health organization (WHO). As per recent statistics (till July 13th, 2021), there are more than 187 million confirmed cases and over 4 million deaths. The rampant nature of SARS-CoV-2 is due to its high infectivity. SARS-CoV-2 is positive-sense single stranded RNA virus. Major structural proteins of SARS-CoV-2 are E, M, N and S proteins. Spike (S) protein is of major interest for vaccine development as this protein recognizes and bind to the receptors (ACE2 receptors) on the host cells. mRNA vaccines are promising alternative to traditional vaccines because of their low manufacturing cost, high efficiency, shorter time required for the development. However, until recently, their inefficient in vivo delivery and instability had restricted their applications on larger scale. Recent advances in in vivo delivery of mRNA and use of modified nucleotides to increase the stability of mRNA provided the grounds for rapid development of mRNA-based vaccine against SARS-CoV-2. Currently, Pakistan lacks such resources and capabilities required for developing mRNA-based vaccines. Therefore, this study is aimed at developing mRNA-based vaccine against SARS-CoV-2. Our study will not only lay foundations for mRNA-based vaccine research in Pakistan but also provide a local resource for combating any future disease outbreaks. The plasmid constructs generated in this study will not be limited to vaccine production against only one variant of SARS-CoV-2, but rather these plasmids can be used as a starting material to produce vaccine against vaccines against any other variants of SARS-CoV-2 or any other pathogen in future.
Meeting ID: 965 4700 8268