Research Goals

1. Understanding the events of graft failure after islet transplantation and addressing these obstacles
2. To study to role of extracellular vesicles or EVs in regulating islet cell function and its impact on graft rejection
3. Train and education graduate, medical and undergraduate students in basic and translational research focusing on pancreatic diseases

Lab Members

Prathab Balaji Saravanan, Ph.D., Assistant Professor, Transplant Surgery

Jagan Kalivarathan, Ph.D., Molecular Lab Tech, Hume-Lee Transplant Institute

Shujauddin Mohammed, Ph.D., Post-doctoral Fellow, Transplant Surgery

Elijah Burch, MS, Islet Lab Tech, Hume-Lee Transplant Institute

Yoshiko Tamura, MS, Lab Manager and QA manager, Hume-Lee Transplant Institute

Research Programs

Research Focus

Anti-inflammatory studies to improve Islet transplant 

Investigating pancreatic cells and related pancreatic diseases have been the major focus of my lab. Pancreatitis and diabetes are both major pancreatic diseases that is a result of an inflammatory assault to the exocrine and endocrine cells of the pancreas respectively. Islet cell transplantation is a promising therapy that can potentially alleviate both the conditions and improve the patient’s quality of life. However, due to multiple destructive factors, the islets transplanted are not fully accepted by the host resulting poor long-term outcomes of this procedure. One such factor is called instant blood mediated inflammatory reaction (IBMIR) which is a reaction when the islets interact with portal blood during islet transplantation. This is comprised of coagulation, complement activation and pro-inflammatory cytokine/chemokine production and infiltration of scavenger innate immune cells. One strategy to reduce the effect of IBMIR has been to reduce overall inflammation by using anti-inflammatory drugs such as Anakinra (Inhibitor for IL-1β) and Etanercept (Inhibitor for TNFα). This has been now clinically used to reduce the impact of IBMIR during islet transplantation. However, this does not completely alleviate the islet cell death caused due to IBMIR. So, we have researched other innovative techniques to incorporate novel anti-inflammatory drugs onto the surface of islets, so they can available to the graft micro-environment.  

Role of EVs and Exosomes in Islet Transplantation 

 Autologous islet cell transplantation is an effective treatment to reduce pain and improve quality of life while restoring glycemic control in patients undergoing pancreatectomy for refractory chronic pancreatitis. Unfortunately, graft function deteriorates gradually and significantly over time. Islets are transplanted back into the portal vein of the liver, but this leads to several stress conditions, including inflammation, hypoxia (due to reduced oxygen in the liver and poor revascularization of islets), and endoplasmic reticulum stress (due to metabolic overload and exhaustion in protein synthesis machinery). All cells including islets release nanosized vesicles called exosomes (EXOs) that carry a unique cargo of proteins and non-coding RNAs such as microRNAs that reflect their pathophysiological status. We think that the EXOs from stressed islets plays a pivotal role in mediating graft failure by instigating inflammation and recruiting immune cells to the transplant site. Islets from a chronically inflamed pancreas (due to chronic pancreatitis) will be severely stressed and thus release EXOs that contain inflammatory mediators. Understanding the fate of these stress-induced islet EXOs and the functional relevance of the cargo released by them is the main focus of this project. The study will initially focus on identifying markers of stress within the EXOs of islet beta cells. An animal model that will facilitate the isolation and tracking of beta cell-specific EXOs will be utilized. We plan to investigate islet beta cell-derived EXOs released in response to each of the stress conditions by in vitro, in vivo, and ex vivo experiments.  

Analysis of patient data and outcome measures from clinical TPIAT cases: 

Lastly, the islet transplant lab provides a clinical service by isolating islet cells for chronic pancreatitis patients that are undergoing the total pancreatectomy with islet auto-transplantation procedure. The process of isolation is a highly specialized technique that is available at only a handful of centers in the nation. Students, Trainees and Post-docs in the lab will be trained on this special technique and become proficient at processing islets from chronic pancreatitis pancreas and normal pancreas obtained from cadavers for research use or for transplantation into type-1 diabetic patients. Apart from the isolation training, students will also have access to isolation metadata and TPIAT pre- and post-transplant metadata that can be used to investigate patient outcomes and correlate with processes that may have an impact. Currently, medical students in my lab are investigating the racial disparity of TPIAT procedure and differences in outcome between Caucasian and African American population. Other studies include looking at pre-transplant patient lab data to predict outcomes of isolation and transplantation that may help physicians in selecting patients for TPIAT. It is possible to publish clinical studies in clinical journals quickly because of the availability of the metadata.

Mentor Statement

I have had the opportunity to mentor some bright post-docs, and undergraduate and high school students. One thing I have learnt is that, self-motivation and dedication of the students towards the research project is key to the student or trainee’s success. That said, our lab accepts highly motivated students and trainees that are interested in clinical, basic and translational research. It is also necessary that the trainees can come up with ideas and suggestions for their research problems, this will ensure building confidence in developing their own research design. Overall, the goal of my mentorship is to prepare you for your future career and create a plan for success.