Dr. Cinar is a trained pharmacist and pharmacologist who joined to the NIAAA/NIH in 2009. Currently, he is a principal investigator and chief of the Section on Fibrotic Disorders in NIAAA. He specializes in cannabinoid receptor pharmacology and the use of liquid chromatography/mass spectrometry for lipid signaling system research. His studies primarily revolve around the endocannabinoid system’s role in metabolic regulation in complex disorders like diabetes, obesity, fatty liver disease, and fibrotic disorders. He also possesses expertise in structure-based drug design, pharmacodynamics, pharmacokinetics analysis, and is keenly interested in employing a polypharmacology approach and functional selectivity strategy to develop more effective and safer therapeutic solutions for intricate fibrotic disorders such as pulmonary fibrosis.
I trained as a pharmacist in Turkey and after I moved to Hungary to do my PhD in Molecular Pharmacology. Following my PhD, I also did a Neurobiology Masters on opioid receptor dimerization and receptor pharmacology. After that, I moved to the Unites States and the NIH for my postdoc. My postdoc research focused on metabolic disorders, more around obesity, diabetes and particularly liver pathologies. Then my interests shifted to pulmonology and particularly lung fibrosis. Now, I have my own lab at NIH focusing on fibrotic disorders combining all of my previous expertise.
My current research focuses on fibrotic disorders in particular to pulmonary fibrosis (PF). One of the interesting aspects is that PF is a multifactorial disease. As we learned from multiple failed clinical trials, conventional pharmacology approaches, based on a one disease – one target paradigm, limits the treatment efficacy in pulmonary fibrosis. This is an important challenge in the field.
My interest is in interested in pursuing a multi-target therapeutic approach to improve treatment efficacy by simultaneously engaging multiple pathogenic pathways in fibrosis with either rational polypharmacology or rational combination therapy approaches. Our approach is to first understand the cellular and molecular mechanisms in PF using cell systems or animal models. We are investigating novel therapeutic targets and modalities. Our goal is to develop effective pharmacotherapies for PF.
As I mentioned even in my PhD I was working on cannabinoid receptor pharmacology and its signalling. In my post doc, I studied in details on how the endocannabinoid system and cannabinoid receptor 1 (CB1R) involves in metabolic regulation in metabolic disorders such as obesity, diabetes, fatty liver disease and fibrosis. It showed me that there are critical roles in the fibrotic process, in obesity, and NASH. For the last 10 years I have been exploring the endocannabinoid / CB1R system in the lungs during lung injury and fibrosis processes.
In the brain, CB1R is essential in the normal physiological state, it is one of the highly abundant receptors in the brain. In the healthy lung, you can barely see CB1R protein expression – its quiescent in the physiological state. But in the case of tissue injury and inflammation of lungs in PF, including lungs in human IPF patients, we can see almost all cell types express high levels of CB1R, and that demonstrates the overactivity . That’s why its so interesting for me to research on why there is a remarkable difference in the pathophysiology.
According to our published and unpublished evidence, Endocannabinoids and CB1R expression increased in the early phase in particularly immune cells. Once it transitioned into fibrosis, the other cell types involving the fibrotic process also highly express CB1R. That’s why our Current research projects focus on investigating cell specific pathogenic roles of cannabinoid receptor 1 (CB1R) activation, and therapeutic use of second and third generation peripheral CB1R antagonists in fibrosing pulmonary diseases including idiopathic pulmonary fibrosis and Hermansky-Pudlak syndrome pulmonary fibrosis.
We have been using the flexiVent for the past 6-7 years. One of the important points for us is the translatability of our basic research into clinic. It is know that pulmonary function parameters are critical to asses the clinical prognosis of PF in patients. That’s why, we measure pulmonary function parameters with the flexiVent in our preclinical animal models. We try to correlate with hydroxyproline, other biochemical markers of PF, or genomics, with pulmonary function. This is important in bridging the preclinical finding to clinical translatability.
In our recently published study, we tried to establish a translational link between the animal model and human disease progression. We integrated the flexiVent parameters with all the other “omics” parameters, and also merged these findings with the human transcriptomics data. I believe this is the only published data so far which integrates pulmonary function parameters in an animal model with transcriptomics data.
Being a scientist, if you think that one day your research may help to cure a disease, this is an amazing motivation and satisfaction. With this motivation, we are really looking to facilitate this preclinical to clinical translation process in our research which could lead to a therapeutic discovery to help patients, this would be very satisfying.
I would suggest that you get different experiences and merge them to find your own niche, this is kind of challenging when everyone is specialized in their own techniques. I feel confident exploring new methodologies and technologies to find complementary approaches. When starting in a research field, you shouldn’t be afraid to explore new methodologies or technologies. On the other hand, in my background I used a lot of analytical tools. Even with the bleomycin model, since I was the new to the field in the beginning, I really tried to establish and find the limitations of the bleomycin model. I found that bleomycin induces heterogenous fibrosis. Even the source of bleomycin generates huge variability. The batch-to-batch variability is a big problem. I strongly suggest spending some time in the beginning to optimize conditions in your own hands and see the limitations and opportunities.
We have identified that dual target therapeutic strategy with inhibiting CB1R and the inducible nitric oxide synthase (iNOS) by an hybrid inhibitor provides improved therapeutic efficacy in different forms of PF. Accordingly, we developed dual CB1R and iNOS inhibitors which is now in a Phase 1 trial. It is certainly an exciting time to see bench to bed translation of our research. A cell specific role of CB1 will help us with cell-specific targeting and that could be a novel therapeutic modality that we can utilize in the future. Additionally, we are currently working on a novel therapeutic target that this research could allow us repositioning one of the clinically safe drug candidates for PF. Hopefully this can have a relatively quick translation into proof-of-concept clinical trials.
