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The Role of the Voltage-Gated Sodium Channel, NaV1.8, in Silent Inflammatory Bowel Disease

Award Number: R01DK122364
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Managing disorders associated with altered perception of abdominal pain remains a major challenge in healthcare. This is particularly true with silent inflammatory bowel disease (IBD), a condition in which individuals with active disease experience little to no concomitant abdominal pain. Silent IBD is common, affecting a third or more of these patients, and can be seen in both major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC). Silent IBD is also very impactful, as these individuals are more than twice as likely to develop serious complications (including strictures, fistulae and abscesses) and to be hospitalized. Unfortunately, currently available diagnostic strategies are limited due to inefficacy, expense and/or practicality. A refined understanding of the mechanisms underlying silent IBD would allow us to develop more effective methods to screen for patients at risk for this condition and could provide insight into novel targets that could be utilized to manage conditions associated with chronic abdominal pain. There is evidence to suggest that voltage-gated sodium channels (VGSC’s) could play a particularly critical role in the development of silent IBD. Previous studies have implicated certain subtypes of these channels as major contributors to transmission of peripheral somatosensory and visceral pain signals. Using targeted exome sequencing in a small IBD cohort, we found that homozygosity for one genetic variant of Nav1.8 (rs6795970; G>A; A1073V) was more common in silent IBD patients. This is notable as one prior study linked this particular polymorphism to hyposensitivity to somatosensory pain stimuli. We hypothesize that Nav1.8 is critical for mediating visceral pain perception and that rs6795970 leads to its dysfunction, resulting in an anti-nociceptive phenotype in IBD. In order to test this hypothesis, we propose to: a) evaluate the frequency of the polymorphism, rs6795970, within larger cohorts of healthy controls, CD and UC patients phenotyped for pain and disease activity, b) assess for changes in visceral and somatic sensation associated with this polymorphism, using barostatic rectal distension and quantitative sensory testing techniques, and c) evaluate for changes in biophysical function of intestinal sensory afferent neurons and pharmacological function of sensory neuron derived cells expressing the mutant channel associated with this polymorphism. These studies are essential as they could identify an objective biomarker to identify patients at risk of developing silent IBD and may provide critical insight into new diagnostic and therapeutic strategies to manage disorders associated with alterations of abdominal pain.


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: 2023 ( Subtotal = $386,863 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/7/2023	NON-COMPETING CONTINUATION	$386,863
														Subtotal = $386,863

Issue Date FY: 2022 ( Subtotal = $401,517 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/5/2022	NON-COMPETING CONTINUATION	$361,366
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/29/2022	NON-COMPETING CONTINUATION	$40,151
														Subtotal = $401,517

Issue Date FY: 2021 ( Subtotal = $378,488 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/1/2021	NON-COMPETING CONTINUATION	$378,488
														Subtotal = $378,488

Issue Date FY: 2020 ( Subtotal = $348,671 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/10/2020	NEW	$348,671
														Subtotal = $348,671

Grand Total All Awards = $1,515,539

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The Role of the Voltage-Gated Sodium Channel, NaV1.8, in Silent Inflammatory Bowel Disease

Award Number: R01DK122364

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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