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Apolipoprotein conformation in amyloid and cardiovascular diseases

Award Number: R01GM067260
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/1998
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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View Award Description

Apolipoprotein conformation in amyloid and cardiovascular diseases - Abstract Aberrant lipoprotein metabolism is a hallmark of obesity that affects >40% of Americans. Obesity and its com- plications, including type-2 diabetes (T2D), cardiovascular, amyloid and severe viral diseases, are the leading causes of premature death. The ultimate goal of this research is to help diagnose and treat these disorders. This project addresses critical unresolved questions in the lipoprotein functionality in obesity. High-, low- and very low- density lipoproteins (HDL, LDL and VLDL) are diverse nanoparticles comprised of lipids and apolipoproteins that direct lipid metabolism in plasma. This process is extremely complex and many details are unknown. Our current focus is on the interactions of lipoproteins and proteins with heparan sulfate (HS), which can trigger both cardio- vascular and amyloid diseases. We will determine the molecular mechanisms of apolipoprotein-HS interactions and altered lipoprotein functionality in obesity. Our powerful approach, which integrates a wide array of biochem- ical, biophysical and computational tools, enabled us to postulate compelling new hypotheses that will be tested in three complementary specific aims. Aim 1 will determine how lipoprotein functionality changes in obesity be- fore and after treatment. Lipoproteins from healthy and morbidly obese subjects will be isolated based on the heparin binding affinity, and their biochemical and functional properties will be determined. Our new hypothesis supported by strong pilot studies will be tested: small particles formed upon action of lipoprotein lipase on circu- lating VLDL provide novel biomarkers of obesity and readouts for treatment. Aim 2 will define the biochemical and functional details of serum amyloid A (SAA) transfer from HDL to LDL in obesity. Our pilot studies indicate that transfer of this small protein induces pro-atherogenic changes in LDL, and suggest two hypotheses that will be tested: i) new mechanistic links between obesity, elevated SAA and atherosclerosis, and ii) novel beneficial role of SAA as a lipid scavenger in obesity. Aim 3 will determine how HS and heparin affect SAA misfolding in amyloid A (AA) amyloidosis, a life-threatening complication of obesity and chronic inflammation. SAA binding to HS is a therapeutic target in AA amyloidosis but molecular details are lacking. Our pilot studies suggest that: i) SAA binding to HS initiates an extracellular pathway of amyloid deposition; ii) periodic anionic arrays in HS bind to stacks of basic residues in amyloid and stabilize amyloid nuclei. To test these intriguing new ideas, we will combine biochemical, biophysical, hydrogen-deuterium exchange mass spectrometry, and computational meth- ods with atomic structures of SAA in crystals and fibrils. Outcome: this research will identify new mechanistic links between obesity and atherosclerosis; verify the hypothetical vital role of SAA as a lipid scavenger; clarify its misfolding pathway in amyloid; and help develop new diagnostic tools and treatments for obesity and related disorders. Broader impact of this research is that it will: i) help understand and modulate the causal link between obesity, T2D and severe COVID-19 disease, and ii) uncover the molecular underpinnings of HS-amyloid inter- actions that can critically impact not only in AA but also Alzheimer's and other major amyloid diseases.


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: 2024 ( Subtotal = $445,637 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	22	8/29/2024	NON-COMPETING CONTINUATION	$445,637
														Subtotal = $445,637

Issue Date FY: 2023 ( Subtotal = $618,480 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	002	21	9/7/2023	SUPPLEMENT FOR EXPANSION	$124,824
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	20	5/3/2023	SUPPLEMENT FOR EXPANSION	$52,010
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	001	21	9/6/2023	NON-COMPETING CONTINUATION	$441,646
														Subtotal = $618,480

Issue Date FY: 2022 ( Subtotal = $436,764 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	002	20	8/31/2022	NON-COMPETING CONTINUATION	$436,764
2022	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	001	19	4/26/2022	COMPETING CONTINUATION	$454
2022	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	18	4/26/2022	NON-COMPETING CONTINUATION	-$454
														Subtotal = $436,764

Issue Date FY: 2021 ( Subtotal = $486,326 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	19	8/26/2021	COMPETING CONTINUATION	$486,326
														Subtotal = $486,326

Issue Date FY: 2020 ( Subtotal = $651,173 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	001	18	8/17/2020	NON-COMPETING CONTINUATION	$427,652
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	17	7/16/2020	SUPPLEMENT FOR EXPANSION	$223,521
														Subtotal = $651,173

Issue Date FY: 2019 ( Subtotal = $427,652 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	17	8/20/2019	NON-COMPETING CONTINUATION	$427,652
														Subtotal = $427,652

Issue Date FY: 2018 ( Subtotal = $381,401 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	001	16	8/30/2018	NON-COMPETING CONTINUATION	$381,401
2018	2016	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	14	5/10/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $381,401

Issue Date FY: 2017 ( Subtotal = $396,753 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	003	15	9/11/2017	COMPETING CONTINUATION	$396,753
2017	2016	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	001	14	1/13/2017	EXTENSION WITH OR WITHOUT FUNDS	$32,575
2017	2016	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	002	14	9/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2015	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	13	1/13/2017	SUPPLEMENT FOR EXPANSION	-$32,575
														Subtotal = $396,753

Issue Date FY: 2016 ( Subtotal = $378,147 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	14	6/20/2016	EXTENSION WITH OR WITHOUT FUNDS	$378,147
														Subtotal = $378,147

Issue Date FY: 2015 ( Subtotal = $464,998 )
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	13	6/18/2015	NON-COMPETING CONTINUATION	$378,147
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	13	6/30/2015	SUPPLEMENT FOR EXPANSION	$86,851
														Subtotal = $464,998

Issue Date FY: 2014 ( Subtotal = $378,147 )
2014	2014	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	12	7/2/2014	NON-COMPETING CONTINUATION	$378,147
														Subtotal = $378,147

Issue Date FY: 2013 ( Subtotal = $378,147 )
2013	2013	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	11	8/22/2013	COMPETING CONTINUATION	$378,147
														Subtotal = $378,147

Issue Date FY: 2010 ( Subtotal = $357,500 )
2010	2010	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	10	6/11/2010	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2009 ( Subtotal = $343,750 )
2009	2009	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	9	8/12/2009	COMPETING CONTINUATION	$343,750
														Subtotal = $343,750

Issue Date FY: 2007 ( Subtotal = $94,151 )
2007	2007	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	8	5/14/2007	SUPPLEMENT FOR EXPANSION	$94,151
														Subtotal = $94,151

Issue Date FY: 2006 ( Subtotal = $280,714 )
2006	2006	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	8	11/25/2005	NON-COMPETING CONTINUATION	$280,714
														Subtotal = $280,714

Issue Date FY: 2005 ( Subtotal = $287,470 )
2005	2005	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	7	11/18/2004	NON-COMPETING CONTINUATION	$287,470
														Subtotal = $287,470

Issue Date FY: 2004 ( Subtotal = $287,470 )
2004	2004	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cell Biology and Biophysics Research	000	6	11/14/2003	NON-COMPETING CONTINUATION	$287,470
														Subtotal = $287,470

Issue Date FY: 2003 ( Subtotal = $273,786 )
2003	2003	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cell Biology and Biophysics Research	000	5		OTHER REVISION	$273,786
														Subtotal = $273,786

Grand Total All Awards = $7,368,466

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Apolipoprotein conformation in amyloid and cardiovascular diseases

Award Number: R01GM067260

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/1998

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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