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Correcting the Cellular Ecology of Diabetic Complications

Award Number: R01DK074095
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: 09/30/2005
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Correcting the Cellular Ecology of Diabetic Complications - PROJECT SUMMARY / ABSTRACT Diabetes affects nearly 10% of the adult population (30 million), and these numbers are expected to double by the year 2050. The pathophysiology of diabetes profoundly impairs all tissue reparative processes, leading to chronic non-healing wounds in affected patients. Diabetic foot ulcers affect between 15-30% of all diabetic individuals and represent the leading cause of lower limb amputations in the United States. Conventional methods to treat diabetes, such as with insulin or oral hypoglycemic agents, can control the disease but do not prevent diabetic complications, as demonstrated by continued progressive organ dysfunction even decades after medical optimization. This highlights a clear need for new therapeutic approaches. Over the past 15 years of NIH funding, our laboratory has made important contributions to our understanding of the critical molecular and cellular pathways in normal and diabetic tissue repair. We have identified hyperglycemia-related impairments in both the local microenvironment and progenitor cell homing and cytokine production that contribute to the pathogenesis of diabetic complications. We have demonstrated that diabetes results in depletion of critical cell subpopulations, resulting in decreased neovascularization and impaired tissue healing. To understand the effects of diabetes on cell population dynamics with greater precision, we have developed novel single cell “-omics” techniques to identify critical perturbations in cell subpopulations at the single cell level. It is our fundamental hypothesis that diabetes alters the “cellular ecology” of heterogeneous cell populations involved in tissue repair and that normalization of those cell subpopulations can treat or reverse diabetic complications. In this proposal, we will integrate emerging multimodal -omics technologies to definitively characterize the behavior of cell subpopulations in diabetic complications, including wound healing. We will extend this work therapeutically by using cell-based approaches to normalize these defects to treat and prevent diabetic complications. To begin, we will employ a novel multiplex approach for high-throughput single cell sequencing to definitively characterize the behavior of resident tissue and progenitor cell subpopulations in human diabetic and non-diabetic wounds (Specific Aim 1). We will then confirm these human observations in animal models and define these changes with spatial resolution by integrating single cell sequencing with next-generation spatial transcriptomic and proteomic technologies and precisely delineate where in the three-dimensional wound environment these differences exist (Specific Aim 2). Finally, we will use this information to optimize the systemic delivery of cell-based therapeutics in order to prevent or reverse diabetes-induced defects in relevant cell populations and thereby correct diabetic complications (Specific Aim 3). Taken together, this novel approach for identifying, spatially characterizing, and correcting subpopulation deficits in diabetic complications will provide new insights into diabetic pathophysiology and inform novel strategies to prevent and treat these complications.


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 = $383,750 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	5/9/2025	NON-COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2024 ( Subtotal = $368,400 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	5/8/2024	NON-COMPETING CONTINUATION	$368,400
														Subtotal = $368,400

Issue Date FY: 2023 ( Subtotal = $383,750 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	4/25/2023	NON-COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2022 ( Subtotal = $383,750 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	5/11/2022	COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	11/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $362,366 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	5/1/2018	NON-COMPETING CONTINUATION	$362,366
														Subtotal = $362,366

Issue Date FY: 2017 ( Subtotal = $362,366 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	4/5/2017	NON-COMPETING CONTINUATION	$326,128
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/13/2017	NON-COMPETING CONTINUATION	$36,238
														Subtotal = $362,366

Issue Date FY: 2016 ( Subtotal = $362,366 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/1/2016	NON-COMPETING CONTINUATION	$362,366
														Subtotal = $362,366

Issue Date FY: 2015 ( Subtotal = $362,366 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/11/2015	COMPETING CONTINUATION	$362,366
														Subtotal = $362,366

Issue Date FY: 2013 ( Subtotal = $450,529 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	5/14/2013	NON-COMPETING CONTINUATION	$450,529
														Subtotal = $450,529

Issue Date FY: 2012 ( Subtotal = $469,196 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/2/2012	NON-COMPETING CONTINUATION	$469,196
														Subtotal = $469,196

Issue Date FY: 2011 ( Subtotal = $471,152 )
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/3/2011	NON-COMPETING CONTINUATION	$471,152
														Subtotal = $471,152

Issue Date FY: 2010 ( Subtotal = $622,398 )
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/12/2010	COMPETING CONTINUATION	$623,172
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	7/15/2010	COMPETING CONTINUATION	-$774
														Subtotal = $622,398

Issue Date FY: 2008 ( Subtotal = $333,960 )
2008	2008	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/17/2008	NON-COMPETING CONTINUATION	$333,960
														Subtotal = $333,960

Issue Date FY: 2007 ( Subtotal = $340,754 )
2007	2007	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/21/2007	NON-COMPETING CONTINUATION	$340,754
														Subtotal = $340,754

Issue Date FY: 2006 ( Subtotal = $350,909 )
2006	2006	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/14/2006	NON-COMPETING CONTINUATION	$350,909
														Subtotal = $350,909

Issue Date FY: 2005 ( Subtotal = $388,700 )
2005	2005	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2005	NEW	$388,700
														Subtotal = $388,700

Grand Total All Awards = $6,396,712

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Correcting the Cellular Ecology of Diabetic Complications

Award Number: R01DK074095

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: 09/30/2005

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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