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Pathophysiological remodeling of the enteric neuromuscular compartment in experimental spinal cord injury

Award Number: R01NS105987
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT The striking physical effects of spinal cord injury (SCI) are most obviously observed as a loss of motor control and sensation below the level of injury. However, neurogenic bowel is one of the most prevalent and clinically recognized comorbidities associated with SCI and is manifested as diminished colonic transit, constipation, evacuation dyssynergy, and overflow incontinence. Colonic dysregulation is recognized as a lifelong physical and psychological challenge for SCI patients and gravely impacts quality of life. The association of SCI with storage and evacuation deficits promotes an inherent tendency to focus upon the loss of supraspinal regulation of somatic and autonomic circuitry of the spinal cord. However, the GI tract is unique in that it has its own extensive intrinsic nervous system, the enteric nervous system (ENS), and has the ability to function quasi- autonomously. Normal colonic transit requires maintenance of the ENS and a syncytium of cells regulating contraction of the smooth muscle to modulate intrinsic reflexes and coordinate gut activity. While the function of the ENS is presumed to be preserved following SCI, the disruption of reflex colonic transit suggests otherwise. While the pathophysiology of neurogenic bowel remains to be understood, studies focusing on GI motility disorders suggest that a loss of enteric neurons, interstitial cells of Cajal (ICC) and fibroblast-like cells (FLC) may be an underlying cause for the majority of these disorders. These cells form the neuromuscular interface through which all smooth muscle activity is regulated. In this proposal we will use an animal model of T3-SCI combined with molecular and cellular techniques as well as in vivo neurophysiological recordings in an aim to define the mechanisms resulting in the loss of enteric nervous system-mediated colonic function post- SCI. Our overarching hypothesis is that spinal cord injury induces colonic dysmotility by reducing the enteric nervous system regulation. We will demonstrate that elevated levels of reactive oxygen species (ROS) precedes the loss of enteric neuromuscular circuits and that ROS scavengers will rescue these cells. Based upon our preliminary observations, we will test the hypothesis that 1) SCI decreases neuromuscular transmission within the colonic smooth muscle after SCI; 2) SCI provokes the loss of ENS neurons, ICC and FLC (neuromuscular remodeling of the colonic syncytium); and 3) SCI provokes impaired anti-oxidant defense of the proximal and distal colon by evaluating elevated ROS levels within the colon and diminished levels of heme oxygenase 1 (HO1), a key anti-oxidant molecule. Our initial expectation is that cholinergic excitatory junction potentials and inhibitory (nitrergic and purinergic) junction potentials will be reduced, thus demonstrating an enteric neuropathy provoking inhibition of colonic transit. These convergent tests of the central hypothesis will provide valuable insight into the inflammatory mechanisms which occur post-SCI and offer therapeutic strategies to reduce such alterations, thereby improving the functional outcome of colonic dysmotility.


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 = $332,958 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/1/2023	NON-COMPETING CONTINUATION	$332,958
														Subtotal = $332,958

Issue Date FY: 2022 ( Subtotal = $333,049 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/15/2022	NON-COMPETING CONTINUATION	$299,744
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/1/2022	NON-COMPETING CONTINUATION	$33,305
														Subtotal = $333,049

Issue Date FY: 2021 ( Subtotal = $333,138 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/13/2021	NON-COMPETING CONTINUATION	$333,138
														Subtotal = $333,138

Issue Date FY: 2020 ( Subtotal = $333,222 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/1/2020	NON-COMPETING CONTINUATION	$333,222
														Subtotal = $333,222

Issue Date FY: 2019 ( Subtotal = $333,304 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/8/2019	NEW	$333,304
														Subtotal = $333,304

Grand Total All Awards = $1,665,671

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Pathophysiological remodeling of the enteric neuromuscular compartment in experimental spinal cord injury

Award Number: R01NS105987

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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