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Neuronal and glial interactions of neuropathic pain

Award Number: R01DE017794
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2006
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Neuronal and glial interactions of neuropathic pain - Mounting evidences suggests that cancers such as melanoma produce programmed death protein-1 ligand 1 (PD-L1) to suppress T cell activation and immunity via interaction with PD-1 (receptor of PD-L1). Emerging immune therapies such as anti-PD1 and anti-PD-L1 treatments have shown great success in treating cancers, such as melanoma and head and neck cancers. However, the unique role of PD-L1/PD-1 in pain regulation is unknown. Our work in progress has demonstrated the presence of anatomical and functional PD-1 in primary sensory neurons and identified PD-L1 as a novel pain inhibitor, produced not only by cancer cells but also by normal neural tissues. We hypothesize that PD-L1 masks cancer pain and inhibits baseline pain and neuropathic pain via silencing PD-1 expressing nociceptive neurons. We also hypothesize that PD-L1 can inhibit somatic and trigeminal neuropathic pain via suppressing microglial and T-cell activation in the spinal cord and brain stem. Of interest recent studies have shown that microglia and T cells in the spinal cord contribute to neuropathic pain in a sex-dependent manner. Consistently, our pilot study shows that intrathecal inhibition of caspase-6 and p38 signaling inhibits nerve injury-induced mechanical allodynia in male but not female mice. We further hypothesize that PD-L1 inhibits microglial and T-cell activation in a sex-dependent manner. The overall goal of this application is to investigate how the PD-L1/PD-1 pathway can mask cancer pain and also suppress neuropathic pain via regulating the function of neurons, microglia, and T-cells. We will use mouse melanoma and neuropathic pain models of both sexes to test our hypotheses by accomplishing the following 3 specific aims: Aim 1. Test the hypothesis that the PD-L1/PD-1 pathway can mask skin cancer pain, suppress somatic and trigeminal neuropathic pain, and inhibit baseline pain; Aim 2. Test the hypothesis that activation of the PD- L1/PD-1 pathway can suppress neuronal excitability in mouse and human DRG/TG neurons and inhibit synaptic plasticity in mouse spinal cord neurons; Aim 3. Test the hypothesis that the PD-L1/PD-1 pathway can inhibit pain via suppressing microglial and T-cell activation in a sex-dependent manner. This project will identify PD-L1 as a novel endogenous pain inhibitor and provide new insights into neuron-glia, neuron-immune, and neuron- cancer interactions. Manipulation of PD-L1/PD-1 signaling may lead to the development of novel analgesics.


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: 2024 ( Subtotal = -$523 )
2024	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Oral Diseases and Disorders Research	000	16	1/24/2024	NON-COMPETING CONTINUATION	-$523
														Subtotal = -$523

Issue Date FY: 2021 ( Subtotal = $488,534 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	001	16	4/9/2021	NON-COMPETING CONTINUATION	$488,534
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	15	3/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $488,534

Issue Date FY: 2020 ( Subtotal = $488,534 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	001	15	7/9/2020	NON-COMPETING CONTINUATION	$488,534
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	14	2/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $488,534

Issue Date FY: 2019 ( Subtotal = $488,534 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	14	9/17/2019	NON-COMPETING CONTINUATION	$488,534
														Subtotal = $488,534

Issue Date FY: 2018 ( Subtotal = $488,534 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	13	5/3/2018	NON-COMPETING CONTINUATION	$488,534
														Subtotal = $488,534

Issue Date FY: 2017 ( Subtotal = $488,534 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	12	3/15/2017	COMPETING CONTINUATION	$488,534
2017	2015	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	001	11	8/21/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $488,534

Issue Date FY: 2015 ( Subtotal = $453,658 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	11	4/17/2015	NON-COMPETING CONTINUATION	$453,658
														Subtotal = $453,658

Issue Date FY: 2014 ( Subtotal = $453,658 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	10	4/17/2014	NON-COMPETING CONTINUATION	$453,658
														Subtotal = $453,658

Issue Date FY: 2013 ( Subtotal = $435,509 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	9	3/21/2013	NON-COMPETING CONTINUATION	$408,293
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	001	9	5/10/2013	NON-COMPETING CONTINUATION	$27,216
														Subtotal = $435,509

Issue Date FY: 2012 ( Subtotal = $444,530 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	002	8	5/2/2012	NON-COMPETING CONTINUATION	$444,530
2012	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	006	6	7/27/2012	COMPETING CONTINUATION	$58,228
2012	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	005	7	7/27/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$58,228
2012	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	004	7	5/4/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$117,060
2012	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	003	7	5/3/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$117,060
2012	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Oral Diseases and Disorders Research	000	7	4/27/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$117,060
2012	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	001	6	4/27/2012	COMPETING CONTINUATION	-$117,060
														Subtotal = $444,530

Issue Date FY: 2011 ( Subtotal = $465,742 )
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	6	4/21/2011	COMPETING CONTINUATION	$465,742
														Subtotal = $465,742

Issue Date FY: 2010 ( Subtotal = $376,462 )
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	5	4/16/2010	NON-COMPETING CONTINUATION	$376,462
														Subtotal = $376,462

Issue Date FY: 2009 ( Subtotal = $380,265 )
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	4	4/8/2009	NON-COMPETING CONTINUATION	$380,265
														Subtotal = $380,265

Issue Date FY: 2008 ( Subtotal = $380,265 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	3	3/25/2008	NON-COMPETING CONTINUATION	$380,265
														Subtotal = $380,265

Issue Date FY: 2007 ( Subtotal = $384,494 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	3/30/2007	NON-COMPETING CONTINUATION	$384,494
														Subtotal = $384,494

Issue Date FY: 2006 ( Subtotal = $395,977 )
2006	2006	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	6/9/2006	NEW	$395,977
														Subtotal = $395,977

Grand Total All Awards = $6,612,707

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Neuronal and glial interactions of neuropathic pain

Award Number: R01DE017794

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2006

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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