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Mechanisms involved in postoperative recovery: a focus on pain, delirium, and neuroinflammation

Award Number: R35GM147094
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Mechanisms involved in postoperative recovery: a focus on pain, delirium, and neuroinflammation - Postoperative recovery in humans varies over a large range and the mechanisms involved are poorly understood. Peripheral monocytes and brain microglia adopt activation states that can be detrimental to inflammation resolution pathways involved in postoperative comorbidities like pain and delirium that impact recovery. The range of activation states correlates to the range of postoperative recovery possibilities observed in both clinical and experimental settings. This potentially explains the inability of researchers and clinicians to adequately predetermine a patient’s pain or delirium outcome after surgery, despite extensive basic and translational studies. The overarching focus of my research program is to identify neuroimmune mechanisms that contribute to variations in postoperative recovery, such as, pain, cognition, and depression, accounting for age and sex. Our approach will combine innovative technologies and relevant pre-clinical experimental models to investigate monocyte/microglia involvement in postoperative recovery with a focus on pain and delirium. In the past 5 years, we have begun to elucidate how age and sex influences neuroinflammatory processes involved in pain and cognitive deficits to inflammatory stimuli, a condition like surgery. We and others have determined that changes in pain and cognitive states in age is related to “priming” of the immune system and not “current” conditions. Building from our current work, over the next five years we propose to: 1) Build a clinically relevant postoperative assessment system to evaluate recovery phases in the context of pain and delirium in rodents. Initial experiments to assess weight loss, body temperature, and ambulatory movement in male and female young and advanced age groups will set an important premise. 2) Determine how age and sex influence monocytes (pain) and microglia (delirium) to modulate neuronal processing is an imperative step toward therapeutic development. We will apply the genomics method of “translating ribosome affinity purification”, (TRAP) to peripheral monocytes and brain microglia. A major strength of TRAP is the ability to identify a cell-specific “functional transcriptome”. This approach utilizes transgenic mice and captures actively translating mRNAs located on ribosomes during protein synthesis. This allows for quantification of translated RNAs using sequencing techniques. An important point of innovation and impact for our proposed work is that the identity of functional mRNAs in immune cells in aging, sex, and surgery will be revealed. Of most interest will be regulation of inflammatory cytokines known to promote pain and/or delirium after surgery. The work proposed is highly innovative because it integrates advanced methods to resolve our understanding of postoperative pain and delirium, to eventually move these molecular insights toward new therapeutic strategies, which aligns with the growing emphasis on human molecular neuroscience in my home department and research center. Our vision is to integrate behavioral and quantitative, cell-type specific transcriptomics to create intuitive descriptions of the diverse recovery outcomes observed postoperatively.


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 = $389,908 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	4	7/21/2025	NON-COMPETING CONTINUATION	$389,908
														Subtotal = $389,908

Issue Date FY: 2024 ( Subtotal = $389,627 )
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	3	7/19/2024	NON-COMPETING CONTINUATION	$389,627
														Subtotal = $389,627

Issue Date FY: 2023 ( Subtotal = $382,712 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	2	9/6/2023	NON-COMPETING CONTINUATION	$382,712
														Subtotal = $382,712

Issue Date FY: 2022 ( Subtotal = $375,788 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	1	8/23/2022	NEW	$375,788
														Subtotal = $375,788

Grand Total All Awards = $1,538,035

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Mechanisms involved in postoperative recovery: a focus on pain, delirium, and neuroinflammation

Award Number: R35GM147094

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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