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Role of cytokines and APOL-1 in the pathogenesis of childhood HIV associated nephrology

Award Number: R01DK103564
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Role of cytokines and APOL-1 in the pathogenesis of childhood HIV associated nephrology - SUMMARY HIV-associated nephropathy (HIVAN) is a renal disease caused by the infection of renal epithelial cells (REc) that is seen more frequently in people of African ancestry who carry two APOL1 risk alleles (APOL1-RA) named G1 or G2. The study of HIVAN provides a unique opportunity to define how contacts between HIV+ inflammatory cells and REc may contribute to establish a kidney HIV-1 reservoir, and to determine how APOL1 interact with HIV-1 to precipitate HIVAN in people of African ancestry. In the first cycle of the grant, we have demonstrated that transmembrane TNF-α (tm-TNF-α) facilitates the infection of podocytes and REc cultured from children with HIVAN, and increases the expression of APOL1 in synergy with HIV-1. We also found that tm-TNF-α and APO1 interact to modulate common pathways involved in endocytosis, HIV-1 trafficking, and degradation in REc. Thus, we hypothesize that tm-TNF-α plays a critical role in the pathogenesis of childhood HIVAN by facilitating the infection of REc through cell-to-cell contacts with mononuclear cells, and by increasing the activity of APOL1-RA in these cells. In HIV+ podocytes, these changes tip their homeostatic balance, impairing key endocytic and autophagic pathways that affect their structure, function, and survival. In turn, these events precipitate HIVAN in children and adults. This hypothesis will be tested in three aims. In aim 1, we will determine how tm-TNF-α modulates the transfer of HIV-1 from mononuclear cells to REc cultured from HIV+ children, and elucidate the mechanisms involved. In aim 2 we will define how tm-TNF−α and APOL1-RA interact in vivo to modulate relevant endocytic and autophagy pathways that are essential for the normal function of Drosophila nephrocytes (the fly equivalent of human podocytes) and for the traffic of HIV-1 particles in podocytes. In aim 3, we will determine how APOL1-RA modulate the infection of podocytes cultured from HIV+ children, and define the risk of children carrying two APOL1 RA to develop HIVAN. In summary, these experiments will elucidate how REc are infected with HIV-1, and interact with renal infiltrating inflammatory cells and the APOL1-RA to establish a renal HIV-reservoir and induce chronic kidney 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: 2023 ( Subtotal = $363,375 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/28/2023	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2022 ( Subtotal = $363,375 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/1/2022	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2021 ( Subtotal = $363,375 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/23/2021	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2020 ( Subtotal = $325,130 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	7	4/1/2020	NON-COMPETING CONTINUATION	$363,375
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	7	4/3/2020	NON-COMPETING CONTINUATION	$0
2020	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	1/18/2020	COMPETING CONTINUATION	-$171,601
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	1/14/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$363,375
2020	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/13/2020	COMPETING CONTINUATION	-$401,620
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	6	3/31/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	6	4/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	1/18/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$171,601
														Subtotal = $325,130

Issue Date FY: 2019 ( Subtotal = $401,625 )
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	7/24/2019	COMPETING CONTINUATION	$171,596
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/4/2019	COMPETING CONTINUATION	$401,625
2019	2017	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/24/2019	NON-COMPETING CONTINUATION	-$171,596
2019	2017	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,625

Issue Date FY: 2017 ( Subtotal = $262,500 )
2017	2017	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/4/2017	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2016 ( Subtotal = $262,500 )
2016	2016	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/23/2016	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2015 ( Subtotal = $258,000 )
2015	2015	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/13/2015	NON-COMPETING CONTINUATION	$258,000
														Subtotal = $258,000

Issue Date FY: 2014 ( Subtotal = $430,000 )
2014	2014	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/24/2014	NEW	$258,000
2014	2014	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVENUE, NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/22/2014	NEW	$172,000
														Subtotal = $430,000

Grand Total All Awards = $3,029,880

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Role of cytokines and APOL-1 in the pathogenesis of childhood HIV associated nephrology

Award Number: R01DK103564

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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