Friday, April 19, 2024 4/19/2024

Novel immunosuppressive mechanism of human bone marrow mesenchymal stem cells in experimental Crohn?s disease

Award Number: K08DK110421
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Crohn’s disease (CD) is chronic intestinal inflammatory disease that affects more than 700,000 individuals in the US and is becoming more common worldwide. The use of biologics such as anti-TNF and anti-adhesion molecule medications has significantly improved the quality of life of CD patients, however biologics tend to lose efficacy with time and have significant side effects. New cell based therapies that utilize the immunosuppressive capacity of adult mesenchymal stem cells (MSC) for immune mediated diseases like CD are currently in clinical trials. A cumulative body of data, including our own work shows that locally injected MSC are a promising therapy for patients with perianal fistulae refractory to anti-TNF’s. However, systemic MSC therapy for luminal CD has lower efficacy, which may be due to myriad reasons with many inadequately investigated. All the murine studies performed demonstrate the benefit of MSC therapy in mouse models that require manipulation to develop inflammation and are focused on treating large intestinal inflammation. Though, nearly two thirds of human CD patients have small intestinal involvement. Thus, there is a critical need to study MSC therapy in disease relevant and preclinical murine models of CD. In this study, we propose to study the SAMP-1/YitFc (SAMP) mouse for treatment with human MSC (hMSC).The SAMP strain is a unique model that spontaneously develops CD-like small intestinal (SI) inflammation which has impressive similarities to the human disease. My strong preliminary data has shown that SAMP mice with established SI inflammation treated with one dose of bone marrow derived human MSC (hMSC) had significantly lower inflammation and had mucosal healing. Therefore, our hypothesis is that hMSC treat SI inflammation in SAMP mice by a mechanism involving the modulation of transcriptome of host tissue to an anti-inflammatory and tissue regeneration pathway. I will test this hypothesis in 2 specific aims. In specific aim 1, we will use the SAMP mice, our new SAMP medical recurrence model, novel techniques including 3D stereomicroscopy (for mucosal healing) to test the subhypothesis that hMSC can treat, prevent SI inflammation and determine the optimal route of hMSC administration. In addition, using a novel hMSC optimized for immunosuppression, we will determine if we can enhance the treatment efficacy of MSC therapy. In aim 2, using human and mouse MSCs transduced with triple reporter, state-of-the-art imaging techniques, laser capture microdissection, single cell RNA sequencing of host cells and MSCs we will investigate the mechanism(s) of healing in SAMP after treatment with MSC. Our preclinical experimental design that tests 1) treatment of established disease, 2) maintenance of remission, 3) the optimal route of MSC administration, 4) use of enhanced immunosuppressive hMSC 5) hMSC effect on mucosal healing, and 6) comparative biology approach to understand the mechanism (s) of healing has high relevance for human IBD. The data generated from this grant will lead to a more mechanistic approach to human clinical trials for treating CD patients and may identify novel molecules that promote tissue regeneration and healing that will form the basis for mechanistic R01s in the future. Thus, we have generated a proposal that builds upon our preliminary findings by generating new scientific ideas that have relevance not only to CD, but potentially to other immune mediated diseases where MSCs are currently in preclinical or early-stage clinical trials.


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 = $81,095 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	8/21/2023	SUPPLEMENT FOR EXPANSION	$81,095
2023	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/21/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $81,095

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/26/2022	NON-COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/29/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $243,284 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	7/21/2021	NON-COMPETING CONTINUATION	$0
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/20/2021	SUPPLEMENT FOR EXPANSION	$81,095
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/15/2021	NON-COMPETING CONTINUATION	$162,189
														Subtotal = $243,284

Issue Date FY: 2020 ( Subtotal = $162,189 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/9/2020	NON-COMPETING CONTINUATION	$162,189
														Subtotal = $162,189

Issue Date FY: 2019 ( Subtotal = $162,189 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/1/2019	NON-COMPETING CONTINUATION	-$164,700
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	8/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$162,189
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	4	8/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,153
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/7/2019	NON-COMPETING CONTINUATION	$164,700
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	4	9/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	8/15/2019	NON-COMPETING CONTINUATION	-$29,153
														Subtotal = $162,189

Issue Date FY: 2018 ( Subtotal = $164,700 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/2/2018	NON-COMPETING CONTINUATION	$164,700
														Subtotal = $164,700

Issue Date FY: 2017 ( Subtotal = $166,200 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/13/2017	NEW	$166,200
														Subtotal = $166,200

Grand Total All Awards = $979,657

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Novel immunosuppressive mechanism of human bone marrow mesenchymal stem cells in experimental Crohn?s disease

Award Number: K08DK110421

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer