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Mechanisms of Trypsin Activation in Pancreatitis

Award Number: R01DK132471
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: 02/09/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Mechanisms of Trypsin Activation in Pancreatitis - ABSTRACT The principal objective of this grant proposal entitled “Mechanisms of trypsin activation in pancreatitis“ is to identify the process by which the digestive protease trypsin becomes activated inside the pancreas and initiates pancreatitis. The premature, ectopic activation of trypsinogen to trypsin is one of the earliest events in the development of pancreatitis. However, the mechanism of intrapancreatic trypsin activation has remained contentious as animal experiments and human genetic studies pointed to different activation pathways. Thus, trypsinogen may be activated by cathepsin B but it can also undergo autoactivation, when trypsin activates trypsinogen. The respective contribution of these two mechanisms to trypsin activation associated with pancreatitis onset is unknown. To address this knowledge gap, we propose three distinct scenarios of trypsinogen activation. 1) In the absence of increased trypsinogen autoactivation caused by genetic mutations, cathepsin B can induce significant intrapancreatic trypsin activation, without affecting pancreatitis severity. (2) If genetic mutations in trypsinogen moderately increase autoactivation, severity of experimentally-induced pancreatitis will depend on the degree of cathepsin B-mediated trypsinogen activation. (3) Finally, if a genetic change that causes robust trypsinogen autoactivation, age of onset and severity of spontaneous pancreatitis is determined by cathepsin B-mediated trypsinogen activation. In this grant proposal, we will test each of these three pathological circumstances using unique mouse models with trypsinogen mutations. Successful completion of the proposed project will offer fresh mechanistic insight into the pathogenesis of pancreatitis and will facilitate the development of novel therapeutic and preventive approaches.


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 = $326,700 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/20/2025	NON-COMPETING CONTINUATION	$326,700
														Subtotal = $326,700

Issue Date FY: 2024 ( Subtotal = $348,480 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$326,700
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/10/2024	NON-COMPETING CONTINUATION	$21,780
														Subtotal = $348,480

Issue Date FY: 2023 ( Subtotal = $363,000 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/9/2023	NEW	$363,000
														Subtotal = $363,000

Grand Total All Awards = $1,038,180

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Mechanisms of Trypsin Activation in Pancreatitis

Award Number: R01DK132471

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: 02/09/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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