Research Description
The primary cilium has emerged in the last decade as a signaling antenna of broad physiological importance. Cilia organize GPCR signaling in olfaction, phototransduction and Hedgehog signaling, and findings of obesity in ciliopathy patients and mouse models demonstrate the central roles of cilia in body weight homeostasis. Central regulators of feeding behavior and ? cell function have recently been found to reside in cilia. I propose to leverage my expertise in ciliary biology to characterize the ciliary signaling modalities that control signaling pathways associated with obesity and diabetes. First, I will characterize how the ciliary trafficking of the melanocortin receptor 4 (MC4R) is controlled by its ligands. Preliminary data indicate that MC4R may be secreted into extracellular vesicles (EVs) at the tip of cilia and we will determine the role of MC4R-EVs in body weight homeostasis. Second, we will we will seek to identify the ciliary pathways that control the activity of the diabetes-related transcription factor GLIS3. These diabetes-related ciliary signaling pathways remain largely unexplored and are poised to yield actionable insights that can be transformed into therapeutic strategies, for example by potentiating the ciliary signaling of MC4R, or by activating GLIS3 and restoring ? cell robustness.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?My longstanding interest lies in the primary cilium, a fascinating little antenna of the cell that senses and transduces a variety of signals. The importance of cilia in obesity and diabetes is evidenced by the ciliopathy Bardet-Biedl Syndrome. BBS patients are severely obese, yet rarely present with diabetes because BBS mutations improve beta cell function and glucose tolerance. We still lack a precise molecular understanding of the signaling events at the primary cilium that regulate body weight homeostasis and beta cell function. I propose to fill this critical knowledge gap in order to unlock novel therapeutic strategies for obesity and diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?Dating back to the purification of insulin a hundred years ago, talented biochemists have made lasting contributions to improve the life of patients with diabetes. Modern tools have enabled researchers to probe the inner workings of the cell with unprecedented depth and precision. I am a biochemist and cell biologist who has studied a little antenna of the cell named the primary cilium for the past 12 years. With the realization that primary cilia play a central role in diabetes and the regulation of body weight, I am committed to dissect the mechanisms by which cilia regulate hypothalamic neurons and ? cells. I expect that my research will offer novel and unsuspected insights that will help address the unmet need of diabetic and obese patients.
Why important for you, personally, to become involved in diabetes research? What role will this award play?My interest in diabetes is very personal as my maternal grandfather passed away from diabetes-related complications and my mother was diagnosed with type 2 diabetes five years ago. This close exposure to the realities of living with diabetes have made me realize the limitations of current treatments and motivate me to apply my talents towards finding a cure for this disease. Another eye-opening experience came from my participation in the annual conference of the Bardet-Biedl Syndrome Family Association last year. Parents shared stories of the insatiable hunger that their children experienced. Many families had to install locks on fridges to prevent access to food in the middle of the night. The treatment options remain non-existent for BBS patients and many other obese patients. My entry into the field of diabetes and obesity research will naturally extend my research program from its fundamental roots in the biology of primary cilia to the clinically important signaling receptors that regulate body weight homeostasis and ? cell function at the primary cilia.
In what direction do you see the future of diabetes research going?I see the ability that stem cell researchers have to grow islets in a dish as one of the greatest promises to diabetes patients. This area of research is already very mature and poised for imminent therapeutic applications. At the other end of the spectrum lies the most basic research in understanding mechanisms of obesity and diabetes. Traditional human genetics and the study of genetic risk factors have uncovered novel genes associated with diabetes and obesity. For most of these genes, we do not know how they influence beta cell function or body weight regulation. I believe that these knowledge gaps can be filled by basic scientists to generate new therapeutic avenues.