The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, plays a critical role in the regulation of physiological responses to both internal and external stimuli. While systemic physiological and pharmacological studies provide evidence of a neural contribution to key metabolic processes such as gluconeogenesis, glycogen storage and lipolysis, there is still relatively little known about the neuroanatomy, neurophysiology and molecular biology of the sensory, parasympathetic and sympathetic fibers associated with peripheral tissues, such as the liver and pancreas, Importantly, we still do not know the functional neuronal circuits involved in regulating key metabolic processes involved in metabolic homeostasis.
Detailed neuroanatomical mapping of neurons and neural circuits in the pancreas, liver and adipose tissue is not available. Cell-specific molecular characterization of the neurons in individual tissues or functional connectivity of neurons within these tissues has not been investigated. Defining cellular and circuit-level function is dependent on detailed knowledge about the components and structure of the circuit, including anatomical position, neurotransmitter content, dendritic and axonal connects, receptor profile, role of glia and electrical properties. Approaches used to identify cell-specific function in the central nervous system (CNS) are only recently being applied to the ANS. Recent data suggest that the application of optogenetics and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to the peripheral nervous system is not straightforward due to the diverse and unique characteristics of the peripheral tissues innervated by the ANS. Other common methodologies used for the CNS, such as the use of tissue slices, may also be applicable to the ANS. Therefore, the development of new or modification of existing, tools and methodologies that can be utilized to elucidate the role of the ANS in peripheral metabolism would significantly advance scientific exploration of this important area.
In addition to the basic neuroanatomy and neurobiology of the ANS, many scientific questions and gaps remain unanswered regarding the functional role of the ANS in metabolism. Little is known about how changes in the individual branches of the ANS contribute to maintaining metabolic homeostasis during the development of obesity, type 2 diabetes or hepatic steatosis. For example, it is still not clear whether parasympathetic nervous system activity is increased or decreased with increased adiposity or how to reconcile the role of the sympathetic nervous system in obesity in the context of both increased lipolysis and fat deposition. Neural feedback loops involving sensory afferents which monitor changes in the metabolic milieu are likely to influence efferent pathways that regulate metabolic function. Therefore, one would predict temporal changes in the neural control and contribution to tissue function and metabolic homeostasis in the progression from normal physiology to the onset of disease to overt pathology. Hypoglycemia-associated autonomic failure, a consequence of repeated iatrogenic hypoglycemic due to insulin therapy, is known to influence the counter-regulatory responses necessary to establish glucose homeostasis. Methodologies that facilitate the measurement of tissue-specific autonomic neural activity and function within the context of chronic animal models of metabolic disease will greatly contribute to our understanding of how the ANS regulates end organ function and is of primary importance in the development of therapeutics to treat disease.
With this FOA, the Division of Diabetes, Endocrinology and Metabolism within the National Institute of Diabetes and Digestive and Kidney Diseases is calling attention to this fundamental, but difficult, area of science as particularly amenable to multidisciplinary teams of outstanding scientists with expertise in neuroscience, metabolism and autonomic nervous system physiology and function. Additional expertise in data analysis and integration would also be recommended. Projects should focus on end organs or tissues that play a significant role in maintaining metabolic homeostasis or are known contributors to metabolic dysregulation. Tissues of interest include: liver, pancreas, adipose tissue and bone. Applications focusing on other tissues are not responsive to this FOA.
Applications should propose to develop and validate novel tools or methodologies to facilitate the detailed analysis of complex circuits and provide insights into cellular interactions that underlie metabolic processes. The new tools and technologies should confer a high degree of cell-type and/or circuit-level specificity. Alternatively, applications may focus on key hypothesis or scientific questions that address the role of the ANS in metabolic diseases. Validation of the utility of the tool/technology within the context of the functional significance of the circuit or metabolic process is considered a required component of all applications.
Applications focusing on neuroanatomical and histological methods or tools should strongly consider investigating human tissue in addition to tissues derived from animal models.
Examples of Potential Projects:
- Development of novel or improved methods (genetic or non-genetic) to deliver active agents such as channel markers or light-sensitive markers to targeted peripheral sensory or efferent neurons innervating end-organs contributing to metabolic homeostasis.
- Single cell analysis of peripheral autonomic neurons in tissues regulating metabolism including methods of disassociation of neurons to facilitate single cell analysis and the identification of cell-specific markers.
- Identification of functional afferent-efferent neuronal circuits that mediate key metabolic processes such as hepatic glucose production, lipolysis or beiging of adipose tissue
- In vitro or in situ systems to investigate the signals necessary for development of parasympathetic or sympathetic neurons from induced pluripotent stem (IPS) cells including co-culturing of neurons with islets, hepatocytes, adipocytes or osteocytes
- Development of methods to measure specific tissue-targeted peripheral neural activity or specific tissue function in response to neural stimulation, including implanted sensors in chronic models of metabolic disease.
Scope and Specific Requirements
The scope of this FOA includes, but is not limited to, the following:
- Groundbreaking, innovative, high impact and cross-cutting research projects that will improve and accelerate biomedical research.
- Basic, clinical and translational projects that could fundamentally enhance the research enterprise and that require the participation, interaction, coordination and integration of activities carried out in multiple research laboratories.
- Creation of large scale unique resources and/or development of transformative technologies that can benefit a wide range of investigators.
- High-impact discovery-based and hypothesis-generating science.
RC2 projects are not intended to support:
- Traditional investigator-initiated, hypothesis-driven and highly focused studies (best supported by the R01 or P01 mechanisms).
- Research that is a logical extension of ongoing work.
- Core (or related) services to supplement the budgets of existing R01-type efforts.
- Applications with a major emphasis outside of the mission of the NIDDK.
Prior Consultation with NIDDK
Consultation with NIDDK staff at least 3 months (and preferably 6 months) prior to the application due date (including resubmission applications) is strongly encouraged for submission of the High Impact, Interdisciplinary Science in NIDDK Research (RC2) application. If requested, NIDDK staff will consider whether the proposed RC2 meets the goals and mission of the Institute; whether it addresses one or more high priority research areas; and whether the application is best fit to the RC2 activity code (or could the proposed work be supported efficiently through traditional NIH funding mechanisms such as a large multi-PI R01).
NIDDK staff will not evaluate the technical and scientific merit of the proposed project; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA. During the consultation phase, if the proposed project does not meet NIDDK’s programmatic needs or is not appropriate for this FOA, applicants will be strongly encouraged to consider other Funding Opportunities.
Deadlines: November 1, 2018; May 30, 2019; October 31, 2019; June 2, 2020; November 3, 2020; June 1, 2021 (letters of intent due 6 weeks prior to the deadline)
Filed Under: Funding Opportunities