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Regulation of Mesenchymal Progenitor Cell Fate and Adipose Tissue Remodeling

Award Number: R01DK120982
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: 04/09/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Regulation of Mesenchymal Progenitor Cell Fate and Adipose Tissue Remodeling - SUMMARY Metabolic diseases are rising around the world as changing diets have led to striking increases in obesity rates. Co-morbidities including coronary artery disease and type 2 diabetes drive massive increases in medical costs and are leading causes of death worldwide. Adipose tissue is crucial for safely sequestering lipids to protect other organs as obesity progresses. Unhealthy expansion of adipose tissue due to genetic or environmental factors leads to increased inflammation and drives the progression of metabolic disease. Therefore, understanding the adipose tissue remodeling process in response is crucial for the development of novel therapies to promote metabolic health and reduce chronic inflammation. Mesenchymal progenitor cells (MPCs) are a heterogeneous cell population in adipose tissue that respond to environmental and metabolic cues to regulate various processes including adipogenesis, immune cell activity and fibrosis. We have found that during obesity progression, MPCs undergo a cell fate switch into cells with properties similar to cancer associated fibroblasts (CAFs). This CAF-like population expresses hallmark CAF genes including the transcription factor SOX4 and the pleotropic growth factor Midkine (MDK) that likely regulate adipogenesis and inflammation in adipose tissue. Importantly, both SOX4 and MDK levels correlate with type 2 diabetes status in humans. Our central hypothesis is that the induction inflammatory CAF-like cells in adipose tissue promotes maladaptive inflammation and decreases proper adipose tissue function. Specific Aim 1 investigates the role of the transcription factor SOX4 in driving MPC phenotype switching and adipose tissue remodeling during the development of obesity and insulin resistance. Specific Aim 2 investigates the role of MDK in regulating immune cell activity and adipose tissue function. Overall, these studies will provide insight into how adipose tissue remodels during the development of obesity, leading to an unhealthy metabolic profile and systemic inflammation that can drive the progression of cardiometabolic complications and other pathologies. Understanding these processes may uncover new therapeutic strategies for metabolic disease.


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: 2026 ( Subtotal = $780,814 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	1/13/2026	NON-COMPETING CONTINUATION	$780,814
														Subtotal = $780,814

Issue Date FY: 2025 ( Subtotal = $780,814 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/27/2024	COMPETING CONTINUATION	$679,308
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/26/2025	COMPETING CONTINUATION	$101,506
														Subtotal = $780,814

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $548,214 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$54,821
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/6/2022	NON-COMPETING CONTINUATION	$493,393
														Subtotal = $548,214

Issue Date FY: 2021 ( Subtotal = $548,214 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/4/2021	NON-COMPETING CONTINUATION	$548,214
														Subtotal = $548,214

Issue Date FY: 2020 ( Subtotal = $548,214 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/26/2020	NON-COMPETING CONTINUATION	$54,821
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/23/2020	NON-COMPETING CONTINUATION	$493,393
														Subtotal = $548,214

Issue Date FY: 2019 ( Subtotal = $493,083 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/9/2019	NEW	$493,083
														Subtotal = $493,083

Grand Total All Awards = $3,699,353

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Regulation of Mesenchymal Progenitor Cell Fate and Adipose Tissue Remodeling

Award Number: R01DK120982

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: 04/09/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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