The research focuses on the dynamical mechanisms of immune cells and their contribution to immunotherapy, regeneration medicine, and cardiovascular disease progression.
Immune cells are exposed to biochemical signals and biomechanical cues within their immediate cellular microenvironment. The focus of the research is geared towards understanding the dynamical mechanisms of immune cells in response to these signals and cues in the areas of immunity, cardiovascular disease and tissue regeneration using a combination of approaches such as, traditional immunobiological assays, live-imaging, quantitative computational biology, and microfluidics.
Circumventing Coronary Heart disease through Immunomodulatory Mechanobiology
Healthcare is one of the key sectors of the Abu Dhabi 2030 Plan, and cardiovascular diseases accounted for more than 37.5% of deaths in 2011 in the United Arab Emirates, with a good proportion of these cases having atherosclerosis, or narrowing of blood vessels from the accumulation of plaque, as the underlying cause. Our goal is to provide new insights into the mechanisms of atherosclerosis, through these three broad objectives: (1) optimize a prototype microfluidic platform that facilitates invitro atherosclerotic plaque formation under dynamic conditions and bring high throughput capabilities to the current design; (2) mechanistically, investigate the role of the cellular microenvironment in the participation of endothelial, smooth muscle, and immune cells in atherosclerotic plaque formation; and (3) elucidate the effectiveness of gold based nanoparticles for improved atherosclerosis treatment. The proposed research conforms closely with the mission of Khalifa University “to make distinctive contributions to important societal challenges through initiative-based research programs and by nimbly assembling multidisciplinary teams to provide timely solutions with a significant regional impact”. The successful meeting of objectives will academically synergise concepts from different disciplines to provide insights into the mechanisms of atherosclerosis from a mechanobiology perspective, and present patients with improved treatment options, and commercially innovate a microfluidic lab-on-chip device for basic research and translational personalized medicine. Principles from cell biology, mathematical and computational biology, biophysics, microfluidic design and fabrication, and tissue engineering converge in this proposed research. Through our research, we strive to make an impact in reducing the risk of death due to cardiovascular diseases not just in the emirates, but globally, aiding in the university’s endeavors of serving society.
Funding: Khalifa University Internal Research Funds 2013 (Sep) – 2015 (Dec), awarded: AED1,435,700
Principal Investigators: Dr. Deborah Gater, Dr. Yanthe Pearson, Dr. Jeremy Teo
Collaborators:Dr. Nicolas Christoforou, Dr. Murat Yapici
Associates: Sara Azzeh, Amany Alkhoury Daria Belik, Kinza Islam
Graduate students: Sara Timraz (MSc awarded Dec 2015)
As with the common trend world wide, the societal burden of cancer and its associated health care costs is increasing in the UAE and it is the third leading cause of death in the country. T-cell immunotherapy for the treatment of cancer is an attractive alternative for the current standard of care, using non-specific cytotoxic agents that collaterally cause damage to normal cells. There are two approaches to produce cancer specific T-cells for the adoptive transfer into patients, the first involves the excision of autologous tumor mass, followed sequentially by isolation, selection, and expansion of specific tumor infiltrating T- cells; the second approach genetically engineers T-cells to specifically recognize tumor associated antigens. These cells are reintroduced into cancer patients, trained and primed to seek out cells that express cell surface antigens, and executing their immunological functions. Results from clinical outcomes have been mixed, and multiple theories have emerged, all pointing towards the inherent immunosuppressive nature of the tumor microenvironment, which involves the dynamic cross talk between the multiple cell types, their associated secreted proteins into a pool of cytokines, and their combined effects on the extra cellular matrix (ECM). There has been no detailed mechanistic study that correlates specific components of the tumor microenvironment to the suppression of natural immunity, we therefore aim to shed light on factors that are detrimental to the success of T-cell immunotherapy treatment of cancer, through fulfilling the aims of this proposal.
Funding: Al Jalila Foundation Seed Grant 2014 – 2016, awarded: AED272,425
Principal Investigators: Dr. Nicolas Christoforou, Dr. Yanthe Pearson , Dr. Jeremy Teo
Collaborators: Amanda Lund (OHSU)
Metastasis is the deadliest aspect of cancer. It is the phenomena whereby cancer cells escape the primary tumor mass, transmigrate across interstitum space, seed themselves into distant secondary sites, and finally forming metastatic tumors. The escape of cancer cell from tumor mass, through epithelial-mesenchymal-transition (EMT), and its subsequent preferential migration towards the blood and lymphatic vessels, are dependent on the dynamic rearrangement of the cytoskeleton. The cytoskeleton is a complex network of proteins whose dynamic state is a balance between the internal biochemical cellular machinery, responding to the external biochemical cues and biomechanical forces that the cell is exposed to. Metastatic cancer cells have been reported to be less ‘stiff’, a physical property contributed by the cytoskeleton, as compared to non-metastatic cells. As with most chemotherapeutic drugs, they have low specificity for cancer cells. To manage the severity of side effects, a suboptimal dosage and consequential prolonged administration of the chemotherapeutic dugs, is often the strategy adopted. Inevitably, the cancer cells will gain resistance to the drugs, progressively diminishing the efficacy of chemotherapeutics. In this proposal, we plan to develop a biomimetic high throughput device that facilitates the biomechanical analysis of cancer cells under live imaging microscopy. The device will be used to screen the effects of novel drug delivery vehicles specific for cancer cells, using a non-invasive method for evaluating cellular biomechanics. We also intend to initiate preliminary experiments on mice cancer models for further validation.
Funding: Terry Fox Foundation 2014 – 2015, awarded: AED135,000
Principal Investigators: Dr. Sungmun Lee, Dr. Murat Yapici, Dr. Jeremy Teo
Graduate Students: Ghada Alhussein (MSc awarded Dec 2015)