2014 — 2017 |
Resch, Jon |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Agrp Neurocircuitry Regulating Energy Expenditure @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): How the brain maintains energy homeostasis is not well understood making it a critical area of research. Agouti-related peptide (AgRP) neurons located in the arcuate nuclei (ARC) of the hypothalamus are essential for the regulation of energy balance. Specific activation of these neurons through pharmacogenetic stimulation produces intense hunger as well as a rapid decrease in energy expenditure. Remarkably, little attention has been paid to the mechanisms producing suppression of energy expenditure by AgRP neurons, leaving the downstream circuitry mediating this effect unknown. This is due, in part, to the complex circuitry that exists within the ARC, where AgRP neurons exist among other neurons of opposite or unrelated function that also share partial overlap in circuitry. To unravel the process by which AgRP neurons function to decrease metabolism, there must first be an understanding of the circuitry mediating the physiological response to AgRP neuron activation. Traditional tract tracing methods are incapable of cell-specific targeting and assessment of functional connectivity, however, recent development of innovative optogenetic and pharmacogenetic technologies now permit the study of complex circuits controlling feeding behavior and metabolism. By utilizing Cre-dependent gene-targeting approaches in transgenic mice, this application proposes to map sites downstream to AgRP neurons and identify the specific neuronal population responsible for AgRP- mediated suppression of energy expenditure. Subsequently, a combination of pharmacogenetic and optogenetic tools will allow for isolated manipulation of specific AgRP synapses to reveal the necessary and/or sufficient efferent targets that mediate suppression of energy expenditure. The findings generated from these studies will provide a wiring diagram for AgRP-mediated suppression of energy expenditure, which could provide insight into potential contributions to a wide range of metabolic diseases, ranging from eating disorders to obesity.
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0.915 |
2019 — 2021 |
Resch, Jon |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Central Regulation of Sodium Appetite Via Synergistic Action of Raas-Sensitive Neurons @ Beth Israel Deaconess Medical Center
PROJECT SUMMARY The motivation to consume sodium, often referred to as sodium (or salt) appetite, is a hard-wired neural response to sodium deficiency regulated by the Renin-Angiotensin-Aldosterone System (RAAS). Impaired function of this system results in inappropriate sodium ingestion that can have deleterious effects on cardiovascular health. The studies and career development activities in this K99/R00 proposal are designed to provide the candidate, Dr. Jon Resch, with the training necessary to become an independent investigator with a research program examining the neural control of sodium appetite. Recently two RAAS-sensitive neuronal populations have been shown to regulate sodium appetite: aldosterone-sensing neurons in the nucleus of the solitary tract (NTSHsd11b2 neurons) and a subpopulation of angiotensin II (AngII)-sensing neurons in the subfornical organ (SFO). Importantly, both NTSHsd11b2 neurons and AngII-sensing SFO neurons are necessary for deficiency-induced sodium appetite, and NTSHsd11b2 neurons require concurrent AngII signaling to drive rapid and robust sodium consumption. Furthermore, both RAAS-sensitive populations promote sodium ingestion via projections to the ventral lateral bed nucleus of the stria terminalis (vlBNST). This strongly suggests that the vlBNST is the critical site where neural processing occurs to coordinate sodium appetite. However, the functional complexity and neurochemical heterogeneity of the vlBNST poses a significant challenge to finding and investigating the neurons within it that regulate sodium appetite. In order to elucidate the neural circuits that control sodium appetite, the proposed research will (1) confirm the site of AngII signaling that enables NTSHsd11b2 neurons to drive sodium appetite, (2) decipher the wiring diagram of RAAS- sensitive inputs to the vlBNST, (3) use high-throughput single-cell transcriptomics to generate a molecular census of vlBNST neurons, and (4) identify the molecular signature of vlBNST sodium appetite neurons. The results of these experiments will form the foundation for many future studies regarding sodium appetite control by the BNST and the downstream circuits through which these neurons produce the motivation to consume sodium. The proposed research and training will be conducted within the Endocrine Division of the Department of Medicine at Beth Israel Deaconess Medical Center, and will ensure the Dr. Resch's successful transition to scientific independence. Dr. Resch will receive training in CRISPR/Cas9-based methods for mouse genetic engineering from his primary mentor, Dr. Bradford Lowell, and in single-cell transcriptomics from his advisory committee members, Drs. Evan Rosen and Linus Tsai. Furthermore, through acquiring the aforementioned technical expertise, coursework, attendance of scientific meetings, and lab management training from his primary mentor during the initial K99 award period, Dr. Resch will cultivate an independent research program studying the neural control of sodium appetite.
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0.915 |