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Sensory Cross-Activation in Bowel Dysfunction

Award Number: R01DK121131
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Sensory Cross-Activation in Bowel Dysfunction - PROJECT SUMMARY It is a common occurrence in human that pain is perceived at a remote location away from the diseased organ. This is also true with bowel dysfunction. Patients with inflammatory bowel diseases (IBD) and/or irritable bowel syndrome (IBS) often experience bladder hyperactivity and somatic pain. Understanding the peripheral mechanisms of pain generation and sensory cross-sensitization helps development of therapeutic approaches with minimum central adverse effects to treat pain comorbidity. Peripheral glial cells are gaining increased recognition for their roles in modulating sensory neuron activity. Satellite glial cells (SGCs) of dorsal root ganglia (DRG) reside around sensory neurons and connect sensory neurons through SGC networks. Using Cre-based expression of hM3Dq to activate glial cells by clozapine-N-oxide (CNO), we show that activation of glial cells leads to an enhanced calcitonin gene-related peptide (CGRP) release to the spinal cord, an essential process in spinal central sensitization. Activation of glial cells also facilitates hypersensitivity of the colon, urinary bladder and hind paw in mice. In DRG, TrkB.T1 is expressed by SGCs but not neurons. Calcium (Ca2+) activity is a common pathway mediated by hM3Dq and TrkB.T1 in SGCs. Importantly, using a unique SGC- sensory neuron co-culture system we show that activation of SGCs mediated by TrkB.T1 leads to activation of adjacent sensory neurons that participate in pain processing. We therefore hypothesize that TrkB.T1 mediates glia-neuron interaction and participates in sensory neuron cross-activation and cross-organ sensitization. To test this hypothesis, we will use mice with inducible conditional TrkB.T1 deletion (TrkB.T1cKO) from peripheral glia mainly from SGCs and mice with hM3Dq or hM4Di expression in peripheral glia. We will perform molecular and functional analysis of colon-bladder sensory neuron cross-activation and cross-organ sensitization in these unique mouse lines (Aim 1). The functional roles of TrkB.T1 in SGCs are to increase the levels of Ca2+ to promote gliotransmitter release. We have identified a number of glial mediators that are regulated by TrkB.T1 in SGCs through proteomic screening and transcriptional analysis. We will characterize TrkB.T1-mediated gliotransmission and gliotransmitter-facilitated sensory neuron activation in the context of cross-organ sensitization (Aim 2). Central sensitization not only contributes to colon-bladder cross-sensitization but also underlies viscero-somatic cross-sensitization. We therefore will examine whether TrkB.T1-mediated SGC- sensory neuron crosstalk contributes to CGRP central release and leads to viscero-somatic cross-sensitization (Aim 3). Throughout the three aims, we will use more than one animal models and apply in vivo and in vitro approaches for functional and mechanistic studies. Interestingly, our preliminary data show that TrkB.T1 is sexually dimorphic. We therefore will perform our experiments in both genders. We anticipate revealing the role of TrkB.T1 in glia-neuron interaction to provide insights in understanding the development of cross-organ sensitization and suggest therapeutic targets.


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 = $431,896 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/16/2025	NON-COMPETING CONTINUATION	$43,189
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/27/2024	NON-COMPETING CONTINUATION	$388,707
														Subtotal = $431,896

Issue Date FY: 2024 ( Subtotal = $464,221 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/30/2023	NON-COMPETING CONTINUATION	$435,208
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/13/2024	NON-COMPETING CONTINUATION	$29,013
														Subtotal = $464,221

Issue Date FY: 2023 ( Subtotal = $483,563 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/6/2023	NON-COMPETING CONTINUATION	$48,355
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/2/2022	NON-COMPETING CONTINUATION	$435,208
														Subtotal = $483,563

Issue Date FY: 2022 ( Subtotal = $483,563 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/2/2021	NEW	$483,563
														Subtotal = $483,563

Grand Total All Awards = $1,863,243

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Sensory Cross-Activation in Bowel Dysfunction

Award Number: R01DK121131

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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