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Sickle cell disease gut dysbiosis effects on CNS pain processing

Award Number: R00HL155791
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Sickle cell disease gut dysbiosis effects on CNS pain processing - Research Summary Pain is the most common complication for patients with sickle cell disease (SCD). Patients with SCD suffer from intense acute pain that is associated with vaso-occlusive episodes and chronic pain which frequently has no obvious pathology. Opioids are the main therapy used to treat SCD pain, despite their negative long-term side effects, lack of efficacy, and associated treatment barriers. In order to develop better therapies for SCD pain, a more mechanistic understanding of the neurobiological basis of SCD pain is needed. Very few studies have characterized the role of the brain in SCD pain, despite patient reports of central sensitization and affective co- morbidities, both of which are correlated with increased SCD pain intensity and frequency. The central nucleus of the amygdala (CeA) is a limbic brain region activated by acute pain, chronic pain, and affective disturbances; increased CeA activity is noted in transgenic SCD mice. Our long-term goal is to identify SCD-related factors that increase CeA neuronal activity and pain-like behaviors in order to develop novel SCD pain therapies. This proposal will examine how the gut microbiome influences CeA activity in SCD. Data from germ-free mice show that an intact gut microbiome is critical for normal amygdala function. The gut microbiome of patients and mouse models with SCD differs from that of healthy controls (i.e. exhibit dysbiosis). Anti- or probiotic manipulation of the gut microbiome changes pain-like behaviors and CeA signaling in SCD mice. The specific aims of this proposal will examine the neuronal mechanisms underlying these changes. In Specific Aim 1, we will use fiber photometry to measure background and pain-evoked CeA activity in the following conditions: (A) pseudo- germfree mice recolonized with SCD fecal material, (B) SCD mice that received longitudinal penicillin treatment, and (C) SCD mice that underwent vagotomy surgery. These experiments will allow us to determine the extent and mechanism through which SCD gut dysbiosis affects CeA activity. In Specific Aim 2, we will directly manipulate select populations of CeA neurons to determine how each is involved in dysbiosis-related pain. We will first use optogenetics to inhibit activity of select CeA neurons in pseudo-germfree mice recolonized with SCD fecal material. We will then determine if 5HT2A receptor activity in the CeA contributes to SCD dysbiosis-related pain. Finally, we will identify novel neuronal signaling pathways through which the SCD gut microbiome could be driving pain. These experiments will be the foundation for my independent research laboratory which will study the anatomical and chemical basis of nociception in order to develop personalized therapeutics for individuals suffering from SCD and other chronic pain disorders.


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 = $248,999 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Blood Diseases and Resources Research	000	5	1/21/2025	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2024 ( Subtotal = $303,061 )
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Blood Diseases and Resources Research	001	4	1/29/2024	NON-COMPETING CONTINUATION	$248,999
2024	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Blood Diseases and Resources Research	000	3	12/11/2023	EXTENSION WITH OR WITHOUT FUNDS	$54,062
														Subtotal = $303,061

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Blood Diseases and Resources Research	000	3	1/3/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $801,059

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Sickle cell disease gut dysbiosis effects on CNS pain processing

Award Number: R00HL155791

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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