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Developing a comprehensive model for peripheral nerve stimulation of gastrointestinal function

Award Number: R01DK119795
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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SUMMARY One in five people suffer from some form of functional gastrointestinal and motility disorders (FGIMD), a group of diseases caused by malfunction of the enteric (gut) nervous system (ENS), including irritable bowel syndrome, fecal incontinence, constipation, dyspepsia, and others. Pharmaceutical intervention is largely unsuccessful at managing these conditions. Recently, electrical sacral nerve stimulation (SNS) has emerged as an alternative therapy for FGIMD. However, how the sacral nerves innervate and modulate the ENS is unknown, so clinicians have to resort to one set of empirical stimulation parameters in hopes of relieving different (sometimes opposite) conditions, with very inconsistent outcomes. The objective of this project is to understanding how the sacral nerves innervate and modulate the enteric nervous system. We pose three hypothetical mechanisms through which SNS modulates gut motility: SNS modulates [a] enteric neurons, [b] smooth muscle, and / or [c] intrinsic pacemaker cells. The challenge is that there is no specific tool, such as pharmacological blockers, transgenic animal models, etc., that can distinguish these three hypothetical mechanisms in vivo. To overcome this challenge, we will build the first computational model that integrates the sacral nerves, the ENS, and GI motility. For each hypothetic mechanism, the in silico framework will predict distinct neuron and muscle firing patterns, which can then be experimentally validated in vivo by c-Fos+ immunomapping and intravital colon imaging. The in silico framework will also predict motility patterns during SNS, which will be validated by implantable motility sensors in awake animals. Once the fundamental mechanism of the SNS-ENS interface is understood, we will use the improved in silico model to optimize SNS parameters that maximally increase or decrease colonic motility, followed by in vivo validation. In summary, we will combine computational modeling and in vivo experiments to determine how the sacral nerves innervate and modulate the ENS and GI motility. Our model will provide fundamental understanding of how peripheral nerves interface with an organ, which is generalizable to other types of peripheral nerves such as the vagus nerve. The model will also enable us to test the hypothesis that specific stimulation patterns can be delivered to treat different conditions in the lower GI system, rather than using the current one-size-fits-all, hit-or-miss approach.


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 = $0 )
2025	2022	TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION	21100 ERWIN ST	WOODLAND HILLS	CA	91367	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $479,634 )
2022	2022	TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION	1018 WESTWOOD BLVD	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$479,634
2022	2022	TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION	1018 WESTWOOD BLVD	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	7/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$137,801
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2022	NON-COMPETING CONTINUATION	$0
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/19/2022	NON-COMPETING CONTINUATION	-$137,801
														Subtotal = $479,634

Issue Date FY: 2021 ( Subtotal = $443,652 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/15/2021	NON-COMPETING CONTINUATION	$443,652
														Subtotal = $443,652

Issue Date FY: 2020 ( Subtotal = $448,415 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/2/2020	NON-COMPETING CONTINUATION	$448,415
														Subtotal = $448,415

Issue Date FY: 2019 ( Subtotal = $471,929 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/9/2019	NEW	$471,929
														Subtotal = $471,929

Grand Total All Awards = $1,843,630

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Developing a comprehensive model for peripheral nerve stimulation of gastrointestinal function

Award Number: R01DK119795

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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