Pileggi, Antonello , MD
Modulation of microRNAs in the transplant microenvironment to enhance islet neovascularization
General Research Subject: Both Type 1 And Type 2 Diabetes
Type of Grant: Innovation
Project Start Date: July 1, 2013
Project End Date: June 30, 2015
The benefits of islet transplantation include the restoration of physiologic beta-cell function that is difficult to attain with intensive exogenous insulin. Multiple limitations have been recognized for the liver as a site for islet cells. Novel tissue engineering approaches are opening new avenues for cellular therapies to develop a bioartificial endocrine pancreas. Notably, the success of cellular therapies to replace beta-cell function depends upon their fast revascularization. The complex process of vessel growth and maturation requires the fine-tuned regulation of several genes. MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that mainly negatively regulate gene expression in a post-transcriptional way in multiple cell biology processes. They have the unique capability of controlling complex gene expression networks, which makes them appealing to understand complex biological processes, such as islet neovasculogenesis.
We have identified a pattern of islet miRNAs expression in the peri-transplant period differentially expressed in response to hypoxia. We hypothesize that modulation of the expression of specific microRNAs in the transplant microenvironment will be of assistance in achieving revascularization and enhancing the engraftment of islets into a biohybrid device. By using a device allowing for the delivery of agents directly in the local transplant microenvironment, we propose to exploit the combined effect of silencing and overexpressing selected miRNAs to modulate angiogenesis in vivo.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The benefits of islet transplantation include the restoration of physiologic beta-cell function that is difficult to attain with intensive exogenous insulin. Islets are currently transplanted into the liver of patients with diabetes, but multiple limitations have been recognized for this site, including the loss of large numbers of islets to inflammation and poor oxygen availability in the early period after transplantation. Importantly, rapid formation of new vascular structures (re-vascularization) is essential for the survival (namely, supply adequate oxygen and nutrients) and function (i.e., glucose sensing and real-time insulin secretion) of islet grafts. Vessel growth and maturation require fine-tuned regulation of several genes controlling multiple functions. Micro-Ribonucleic Acids (micro-RNAs or miRNAs) are small non-coding RNAs that mainly negatively regulate (acting like 'brakes') complex gene expression networks in a post-transcriptional fashion, included in angiogenesis.
We have identified a pattern of islet miRNAs differentially expressed in transplanted islets in response to lack of oxygen. Working hypothesis of this Innovative ADA Grant Application is that modulation of the expression of specific microRNAs in the transplant microenvironment will be of assistance in achieving faster and more efficient new vessel formation and enhancing the engraftment of islets, which in turn will result in better function after transplantation. We will test our hypothesis using an implantable device for islet transplantation that allows for the delivery of agents directly in the local transplant microenvironment. To this aim, the impact of silencing (switching off) and overexpressing (turning on) selected miRNAs on the modulation of new vessel formation in islet transplant models will be evaluated. The results of the studies may lead to the development of novel targeted interventions aimed at improving islet transplant outcome in a bioengineered site of implantation.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Tissue engineering approaches are opening new avenues for cellular therapies to develop a biological replacement of endocrine function in patients with diabetes. The ultimate goal of beta cell replacement therapies is to restore beta cell function long-term. Being able to engineering the transplant microenvironment by rendering it most favorable for islet cells would allow for a less traumatic adaptation and possibly a more durable function after implantation. Favoring a prompt and physiological process of new vessel formation in transplanted islets may represent a viable approach to ameliorate the success of islet cell transplantation in the clinical settings, being it through the use of adult islets, or extending it to any other source of beta-cell grafts, being them of animal origin (xenotransplantation) or derived from stem cells.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a very challenging, multifaceted condition affecting several organ systems and the life of many people. I am a physician scientist with a commitment for patient-oriented research endeavors. The importance of achieving tight metabolic control to prevent/delay the dreadful progressive complications of diabetes has been recognized, but this goal is difficult to achieve in the majority of patients using medical therapy. The possibility to restoring physiologic metabolic control beta cell function by islet transplantation is very appealing, and supported by the steady progress of the last 30 years in clinical trials.
Training as a physician gave me the imprinting of willing to improve the ailments of people, and engaging in research gave me the tools and intellectual stimuli to challenge the 'status quo' by exploring in the laboratory novel approaches to overcome clinical hurdles. I have learned that a multi pronged approach is needed to treat and eventually cure diabetes. The same applies to islet transplantation requiring a multidisciplinary efforts involving immunobiology, cell and molecular biology, tissue engineering, endocrinology, surgery, and pharmacology, amongst others. In the recent years, I have begun to explore novel tissue engineering approaches to modify the microenvironment for islet cell transplantation. This ADA Innovation Award will be instrumental to address critical hurdles faced in clinical islet transplantation and help better understand and identify potential molecular targets to improve islet cell survival after transplantation, an area at the very heart of my research interests.
In what direction do you see the future of diabetes research going?
We are living very exciting times with accelerated progress being recorded in the emerging fields of regenerative medicine, tissue engineering, immunotherapy and cellular transplantation. The steady progress of beta cell replacement therapies and the convergence of multiple technology justify cautious optimism for the years to come for a biological therapy for diabetes.
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