Miranker, Andrew , PhD
Molecular determination of the origins of islet amyloid membrane activity
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Apoptosis, Islet Biology\Channels, Islet Biology\Channels, Single Cell Studies, and Calcium Signaling, Other
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
The purpose of the proposed research is to address a current lack of structural details associated with islet amyloid polypeptide (IAPP) activity. IAPP is a protein hormone co-produced with insulin that forms insoluble aggregates. This process is correlated to insulin-secreting cell dysfunction and death in type 2 diabetes and in the failure of islet cell transplants to thrive in type 1 diabetes.
Our hypothesis is that IAPP activity is dictated by specific molecular interactions with other IAPP proteins and cellular membranes. Moreover, it is the structures that form prior to aggregation that allow stabilizing interactions with the lipids of the cellular membrane and other IAPP proteins. It is these events, not aggregation, that cause pathology. Our goal is to elucidate the structure-based mechanism of these processes by correlating functions to specific locations on the protein.
The sequence of IAPP will be altered to generate a series of mutant proteins that can report which portions of the peptide are responsible for activity. Experiments will be conducted to probe the integrity of the cellular membrane in the presence of these altered proteins, the rate at which protein crosses the membrane, toxicity and the site of toxicity in model islet cells. These findings will be coupled to experiments that will map the structure and position of the protein in the presence of model lipid membranes. Consequently, the proposed research will help elucidate a critical and novel molecular origin for dysfunction of insulin-secreting cells.
Mentor: Andrew Miranker, PhD
Postdoctoral Fellow: Diana E. Schlamadinger
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
A central feature of type 2 diabetes is the death and/or dysfunction of insulin-secreting beta cells. In addition to insulin, the beta cells of the pancreas secrete the peptide hormone islet amyloid polypeptide (IAPP), the focus of this research project. Unique to diabetics, IAPP is found to form aggregated deposits in a manner that is correlated with the loss of beta cells. Under laboratory conditions, IAPP can be induced to form closely similar aggregates. Importantly, under the same conditions, IAPP has been demonstrated to be toxic to insulin-secreting cells grown in culture. Clinical observations are supported by five independent rodent lines transgenic for human IAPP. All of these animals and their isolated islets demonstrate a propensity to form aggregates that is correlated with either diminishment of beta cell function and/or loss of beta cell mass.
IAPP takes on a wide range of structures, and it is not clear which structures are responsible for function and which for toxic activity. The experiments described in this research project aim to answer fundamental questions about the specific molecular structures populated when interacting with model cell membranes as well as peptide activity in cellular environments. The findings will directly correlate peptide function to specific molecular substituents and structures. Small molecules currently being designed and synthesized in the Miranker lab will be incorporated into these studies to stabilize peptide structures and elucidate mechanistic information in solution, and in the presence of insulin-secreting cells. Our findings will directly lead to the identification of novel molecules that inhibit the cytotoxic activity of IAPP towards insulin-secreting cells.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our work will deepen the current understanding of the mechanism of the dysfunction of insulin-secreting cells of the pancreas; a central pathology of type 2 diabetes. We aim to resolve and elucidate specific structures of a peptide hormone, IAPP, that are most closely associated with toxicity towards these pancreatic cells. These studies will directly lead to novel targets for drug development. Indeed, as part of our research plan includes the use of synthetic chemistry, it is our hope that we will not only structurally characterize new drug targets, but may also identify potential lead compounds. Subsequent development would then lead to agents that can slow or stop the damage caused to insulin secreting cells in type 2 diabetics.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have dedicated the past 14 years to elucidating the physical chemical basis of protein aggregation. It is plausible, and indeed many labs do, study aggregation as an abstract problem in protein physical chemistry. I have, however, always found it more rewarding to focus my attention on aspects of chemistry of direct relevance to the human condition. The predominant system under study in my laboratory is Islet Amyloid Polypeptide (IAPP) from type 2 diabetes. This protein provides challenges that span physical chemistry through to physiology. Consider, for example, that IAPP aggregates aggressively when isolated under dilute conditions. Yet in vivo, the protein is packaged by cells at concentrations that would cause instantaneous aggregation in solution. Therefore, we have not asked why this protein aggregates in diabetics. Rather, we have asked why it does not aggregate in the healthy.
After many years of study, we have come to a new and important conclusion that aggregates, while easy to observe, are not causal to pathology. Instead, the precursors that allow such aggregates to form are also capable of causing cell death. These recent determination has opened a very new area in which we are strongly focused on specific molecular structures associated with biological membranes. This ADA award is critical to our efforts as it will allow use to fully develop this new focus thereby bringing our attention, and those of other researchers, directly to the molecular structures that we validate to be causal to ß-cell death.
In what direction do you see the future of diabetes research going?
A considerable amount of effort in diabetes research has focused on the systemic problems caused by the disease. At the molecular level, hyperinsulinemia, loss of glycemic control, down regulation of insulin receptors, loss of beta cell mass, etc all lead to a myriad of serious long term health issues. It is possible, however to invert the problem entirely. I believe it will become increasingly apparent that many of the systemic issues observed in diabetics are not causal. Rather, systemic effects in diabetes can be symptomatic of a sick pancreas. i.e. beta cell dysfunction is not only symptomatic of diabetes, but for much of diabetic etiology, it is causal.
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