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Identifying new strategies for prevention of cardiovascular complications of diabetes

Award Number: R35HL150754
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Identifying new strategies for prevention of cardiovascular complications of diabetes - Currently, almost 10% of the US population (over 30 million people) suffer from type 1 or type 2 diabetes mellitus (T1DM or T2DM) and more than 30% have pre-diabetes. Approximately 1.4 million children and adults have T1DM. Because the prevalence of diabetes continues to rise, because both T1DM and T2DM markedly increase the risk of cardiovascular disease (CVD), and because CVD events occur at younger ages in patients with diabetes, it is critical to understand how diabetes increases CVD risk and how CVD can be prevented. Patients with increased CVD risk are generally treated with statins to lower LDL cholesterol. However, even with statin treatment, patients with diabetes have residual CVD risk and a greater incidence of heart attack and stroke than subjects without diabetes. This residual CVD risk in patients with T2DM and elevated triglycerides (TGs) has been linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs). However, TG levels are normal in most T1DM patients, and current dogma maintains that TRLs do not drive CVD risk in these patients. We hypothesize that plasma TGs do not accurately reflect levels of the atherogenic remnant lipoprotein particles (RLPs) derived from VLDL or chylomicrons because RLPs and small VLDL contain much less TG than do TRLs. We have developed a new method to quantify RLPs and small VLDL. Furthermore, our data show that elevated serum apolipoprotein C3 (APOC3) levels predict CVD events in subjects with T1DM when adjusted for diabetes severity and other traditional risk factors; this correlation was found in subjects with normal TGs. APOC3 increases levels of TRLs and RLPs. We have previously reported that TRLs contribute to atherosclerotic plaque instability in mouse models of diabetes. We have also found that diabetes leads to suppression of glycolysis in macrophages, and that this in turn is linked to ER stress and plaque instability. During the next 7 years, this project will reveal mechanisms behind increased CVD risk in humans, focusing on RLPs and APOC3 as CVD risk factors in patients with T1DM and T2DM and TG levels in the normal range. By using our mechanistic mouse models of diabetes-accelerated atherosclerosis, we will also clarify the diabetes- induced mechanisms that promote early and advanced atherosclerosis. As part of these mechanistic studies, we will reveal how diabetes, APOC3 and RLPs alter lesion macrophages, by using proteomics, single cell RNA-sequencing, flow cytometry, and functional assays. By combining prospective studies on CVD risk in humans with diabetes and our mechanistic mouse models of diabetes-accelerated atherosclerosis, we believe we are in an excellent position to fill an important and clinically significant gap in our understanding of how diabetes promotes CVD and to identify new treatment and prevention strategies.


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 = $947,711 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	6	3/14/2025	NON-COMPETING CONTINUATION	$947,711
														Subtotal = $947,711

Issue Date FY: 2024 ( Subtotal = $1,002,374 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	5	6/24/2024	NON-COMPETING CONTINUATION	$81,827
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	5	3/22/2024	NON-COMPETING CONTINUATION	$920,547
														Subtotal = $1,002,374

Issue Date FY: 2023 ( Subtotal = $1,022,830 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	4	4/14/2023	NON-COMPETING CONTINUATION	$1,022,830
2023	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,022,830

Issue Date FY: 2022 ( Subtotal = $1,016,402 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	3	6/29/2022	NON-COMPETING CONTINUATION	$101,643
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	3	3/14/2022	NON-COMPETING CONTINUATION	$914,759
														Subtotal = $1,016,402

Issue Date FY: 2021 ( Subtotal = $1,017,915 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	2	4/20/2021	NON-COMPETING CONTINUATION	$1,017,915
														Subtotal = $1,017,915

Issue Date FY: 2020 ( Subtotal = $1,037,755 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	1	2/25/2020	NEW	$1,037,755
														Subtotal = $1,037,755

Grand Total All Awards = $6,044,987

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Identifying new strategies for prevention of cardiovascular complications of diabetes

Award Number: R35HL150754

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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