Description:
Glucagon, GLP-1 and GIP are related peptides that target G-protein coupled receptors with effects on glucose and lipid homeostasis. Glucagon concentrations can be elevated in diabetes due to dysregulation of glucagon secretion, while the pancreatic beta-cell can be resistant to the insulinotropic effects of the incretins, both contributing to hyperglycemia. GLP-1 mimetics are in widespread use to treat diabetes, and a number of glucagon and GIP receptor antagonists and agonists have also been tested as hypoglycemic agents. Despite the widespread interest in the therapeutic potential of this family of hormones, research regarding their interaction to regulate islet hormone secretion and on other target tissues is hampered through lack of reproducible assays and widely distributed peptide, small molecule and antibody reagents.
The ability to study glucagon secretion, plasma levels and biological activity in response to diet, physical activity, diurnal rhythms, body composition, disease (particularly diabetes) and drug treatment is limited due to nonspecificity of typically used radioimmunoassays. Commercially available ELISA assays have improved the ability to monitor changes in glucagon over time in people and animals, but more specific assays with improved accuracy and reproducibility would make it easier to do cross-sectional comparisons and to monitor small changes in glucagon, or detect it in small volumes of blood.
Recent publications have highlighted the complexity of the roles for glucagon and incretins, and the cellular pathways activated by signaling through their receptors, indicating the need for greater understanding of the biology, physiology and potential clinical relevance. As an example, new dual and triple agonists for the glucagon, GIP and GLP-1 receptors show effectiveness in improving beta cell function and mass in diabetes, casting light on the complexity of the interaction of these receptors. Recent appreciation of the differential roles of glucagon in the liver, adipose and brain suggests that ligands that target specific tissues would be highly useful. Although several chemical classes of glucagon receptor antagonists/inverse agonists have been reported, these compounds are not readily available to the broad scientific community. The increased availability of such ligands would provide tools to understand further the role of glucagon and signaling through the glucagon receptor as well as enhance the study of the pharmacology of the small molecule ligands themselves.
Studies in which the glucagon receptor has been inhibited or genetically ablated show pancreatic islet alpha-cell hyperplasia, increased glucagon secretion and increased exocrine growth. Mechanisms for these observations are not well known, and badly needed research depends on widely distributed high quality, validated reagents for manipulating the receptor in central and peripheral tissues, and for elucidating alpha cell biology.
The unambiguous identification of incretin receptor-expressing cells in humans and animal species is critically important knowledge for fully understanding the biological effects, clinical benefits, and any side effects of treatment with incretin agonists (in particular GLP-1 receptor agonists). In addition to the pancreas, GIP and GLP-1 receptors have been found in the intestine, stomach, kidney, lungs, heart, and brain. However, the accurate localization of incretin receptor expression, especially in normal and diabetic human pancreas, is challenging because most of the current commercially available antisera used for detection of GLP-1 and GIP receptor expression by immunohistochemical techniques and Western blotting often are neither sufficiently sensitive nor specific to yield reliable data. The necessary validation assays for these reagents (antisera) are sometimes omitted. This represents an important problem in terms of the reliability, validity and reproducibility of the published experimental data and their interpretation.
This FOA invites Small Business Innovation Research (SBIR) grant applications from small business concerns for funding to perform research leading to the development of validated, highly sensitive, and specific assays for plasma glucagon; for development and/or wide commercial distribution of reagents for manipulation of glucagon receptor activity in the islet, brain and peripheral tissues; for reagents to be used to improve our understanding of pancreatic alpha-cell biology particularly in response to glucagon and incretins; and for reagents and assays for the accurate expression and quantitation of functional incretin receptors in the endocrine/exocrine cells of the pancreas and relevant extrapancreatic tissues.
Examples of projects that this announcement encourages include but is not limited to:
- Develop, validate, and/or manufacture highly specific, accurate assays for glucagon, for use with human and mouse plasma.
- Develop and/or provide for wide commercial distribution peptides, small molecules or antibodies that can be used to manipulate glucagon receptor activity. These may be specific for different tissues such as islet cells, liver, adipose and brain.
- Develop and validate reagents and assays useful for the study of alpha-cell biology, regulation, function, regeneration and plasticity, particularly in response to manipulation of the glucagon and incretin receptors in obesity and diabetes.
- Develop highly specific and sensitive poly- and monoclonal antibodies for the identification of incretin receptors in tissues.
- Develop reliable validation methods/assays to verify the sensitivity and specificity of incretin receptor reagents.
- Develop novel probes and in situ ligands to improve the detection and quantitation of mRNA and protein expression of functional incretin and glucagon receptors.
- Develop fluorescence-labeled incretin or glucagon analogs for in vivo or ex vivo detection/imaging of receptor expression
