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Characterization of the molecular and cellular mechanisms underlying the sickness symptoms

Award Number: R00NS114107
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT During acute infection, animals display a set of highly stereotyped symptoms which are critical for survival. These symptoms include changes in physiology, such as fever, as well as behavioral changes such as lethargy and loss of appetite. How do sickness symptoms arise? The generation of fever in response to infection has been reported in warm-blooded animals as well as cold-blooded reptiles and even invertebrates, suggesting that evolutionarily-conserved, hard-wired mechanisms exist to bring about fever during an immune response. Changes to thermoregulatory and other homeostatic circuits in the brain are likely required to generate sickness symptoms, but the mechanisms by which immune signals are translated into the brain and into neuronal activity to alter these circuits are currently unknown. I have identified a population of neurons in the preoptic area of the hypothalamus that is highly sensitive to the administration of pro-inflammatory lipopolysaccharides (LPS). In my preliminary experiments, I have found that these neurons are critical for the initiation of fever and they may also contribute to other sickness symptoms such as warmth-seeking behavior and loss of appetite. In work proposed here I will rigorously test the function of this LPS-sensitive neuronal population using the latest tools for behavior- specific cell type manipulation. I will uncover how these neurons regulate fever as well as other sickness symptoms. In addition, I will use viral-mediated tracing tools to uncover the circuit mechanism by which these LPS-sensitive neurons modulate thermoregulatory and feeding circuits. The successful completion of these aims will reveal the first discovered neural circuits that mediate sickness. Many studies have found increased activation of glial cell types in response to LPS or infection, which may be essential for the activation of fever-initiating circuits. In my final aim, I will use the latest technology for molecular cell type identification to uncover the identity of the neurons as well as the subtypes of non-neuronal populations in the preoptic hypothalamus that contribute to the fever response. During my R00 phase, I will identify the non- neuronal populations that are essential for fever initiation and reveal new molecular mechanisms by which these cell types communicate with neurons and thereby generate a fever. The successful completion of this project will provide a platform for future experiments aimed at understanding the cellular and molecular mechanisms underlying the generation of sickness symptoms. The training phase of the award will be conducted in the laboratory of Dr. Catherine Dulac at Harvard University. In addition, I will be mentored by the outstanding team of scientists on my advisory committee that will assist with specific training goals as well as career guidance. In my application I have outlined a comprehensive plan for the acquisition of conceptual, technical and professional skills that will enable my transition to an independent research position.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $203,421 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/12/2024	NON-COMPETING CONTINUATION	$203,421
														Subtotal = $203,421

Issue Date FY: 2024 ( Subtotal = $220,386 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/12/2024	NON-COMPETING CONTINUATION	$15,820
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/6/2023	NON-COMPETING CONTINUATION	$203,421
2024	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	10/12/2023	EXTENSION WITH OR WITHOUT FUNDS	$1,145
														Subtotal = $220,386

Issue Date FY: 2023 ( Subtotal = $237,528 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/26/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$237,528
														Subtotal = $237,528

Grand Total All Awards = $661,335

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Characterization of the molecular and cellular mechanisms underlying the sickness symptoms

Award Number: R00NS114107

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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