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Mechanisms for cell uptake of LDL/DNA complexes

Award Number: SC3GM099637
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: 01/13/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2016

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Mechanisms for cell uptake of LDL/DNA complexes - DESCRIPTION (provided by applicant): Our hypothesis is that low-density lipoproteins (LDL) are natural vectors for foreign and endogenous nucleic acids. These complexes, comprised of LDL and nucleic acids, may gain cell entry through a receptor-mediated pathway that involves LDL B/E receptor binding regions contained in both apo B100 and apo E, protein constituents of all low-density lipoprotein particles. LDL were previously shown to bind nucleic acids and have been successfully used in cell transfection experiments both in vitro and in vivo. The mechanism for cell entry of LDL/Nucleic Acid complexes (LDL/NA) is not known. Our Specific Aim 1 is to determine the mechanism for LDL/DNA complex cell uptake. We will assess the involvement of endocytosis- based mechanisms in the uptake of LDL complexed to plasmid and human genomic DNA. Co- localization of LDL/DNA with the endocytosis markers will be determined. Contribution of the B/E receptor and glycosamino glycans (GAGs) in the LDL/DNA uptake will be characterized using selective blocking of LDL-receptor interaction by various monoclonal antibodies as well as LDL-receptor deficient and GAG-deficient cell lines. Our Specific Aim 2 is to study the intracellular distribution of both LDL and DNA after LDL-mediated cell transfection to address the hypothesis of endosomal escape. We will establish whether DNA is liberated separately or as a complex with the apolipoproteins or fragments thereof and determine the time of these events. Our Specific Aim 3 is to determine the role that Lysine/Arginine-rich regions which contain analogues of the apo E receptor ligand play in endocytosis and intracellular transit of nucleic acids. We will determine if sites on apo B100 other than putative B/E receptor-binding region are involved in the uptake of LDL/DNA. Three regions of apo B100 (0014-0096, 0583- 0614, and 3182-3215) have been identified as potential B/E receptor binding sites based on presence R/K-rich motifs similar to those in to apo E and in Flaviviridae proteins. Synthetic peptides spanning these regions of Apo B100 were shown to bind or enter HeLa cells in our preliminary studies. We will determine if these peptides compete with LDL/DNA for cell entry, and if monoclonal antibodies to these regions of apo B100 affect the uptake of LDL/DNA. This project will advance our understanding of the natural function of LDL as nucleic acid delivery vector.


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: 2017 ( Subtotal = -$3,606 )
2017	2014	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	2102 TREASURE HILLS BLVD STE 3.100	HARLINGEN	TX	78550	CAMERON	USA	Biomedical Research and Research Training	001	4	2/6/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$4,220
2017	2014	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	3	2/6/2017	NON-COMPETING CONTINUATION	$614
														Subtotal = -$3,606

Issue Date FY: 2016 ( Subtotal = $3,606 )
2016	2014	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	3	6/23/2016	NON-COMPETING CONTINUATION	-$84,020
2016	2014	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV)	1201 W. UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	4	8/5/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,626
2016	2014	UNIVERSITY OF TEXAS RIO GRANDE VALLEY (UTRGV), THE	1201 W. UNIVERSITY DR	EDINBURG	TX	785392909	HIDALGO	USA	Biomedical Research and Research Training	002	4	8/11/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $3,606

Issue Date FY: 2014 ( Subtotal = $87,626 )
2014	2014	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	3	11/26/2013	NON-COMPETING CONTINUATION	$78,863
2014	2014	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	001	3	2/28/2014	NON-COMPETING CONTINUATION	$8,763
														Subtotal = $87,626

Issue Date FY: 2013 ( Subtotal = $84,559 )
2013	2013	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	001	2	5/31/2013	NON-COMPETING CONTINUATION	$5,696
2013	2013	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	2	11/23/2012	NON-COMPETING CONTINUATION	$78,863
														Subtotal = $84,559

Issue Date FY: 2012 ( Subtotal = $87,384 )
2012	2012	UNIVERSITY OF TEXAS AT BROWNSVILLE	80 FORT BROWN	BROWNSVILLE	TX	78520	CAMERON	USA	Biomedical Research and Research Training	000	1	1/13/2012	NEW	$87,384
														Subtotal = $87,384

Grand Total All Awards = $259,569

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Mechanisms for cell uptake of LDL/DNA complexes

Award Number: SC3GM099637

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: 01/13/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2016

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