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Extracellular vesicles derived from amniotic fluid stem cells normalize glomerular function during progressive kidney disease.

Award Number: R01DK121037
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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During the progression of most chronic kidney diseases (CKD) podocytes and glomerular endothelial cells (GEC) are irreversibly damaged. Injury to these cells or changes within the composition of the glomerular basement membrane lead to alterations of the structure and function of the glomerular filtration barrier (GFB). Re- establishing GFB function by stimulating endogenous repair mechanisms could slow kidney disease progression. Data presented in this proposal show that extracellular vesicles derived from human amniotic fluid stem cells (hAFSC-EVs) are renoprotective in vivo in our animal model of CKD, Alport Syndrome (AS). No side effects or stimulation of an immune response occurred. These EVs can activate repair mechanisms in glomerular cells by cargo transfer. Specifically, they modulate the levels of miR-93 in both podocytes and GEC. miR-93 plays a key role in CKD since changes in its expression level are associated with the development of renal damage and fibrosis; specifically, miR-93 expression is decreased in mouse and human AS glomeruli and urine samples and hEVs can restore miR-93 levels to normal. We hypothesize that hEVs can re-establish glomerular function by preventing further glomerular injury, thus minimizing renal disease progression. Using transgenic Alport mice, EVs of human origin, and human AS biopsies combined with an innovative spatial transcriptomics approach, we will study the EV mechanism of action with specific focus on the ability of the EV/miR-93 axis to “re-program” cellular signaling networks that regulate glomerular cell biology. We also aim to evaluate the disease modifying capability of hEVs at different AS stages (Aim 1). Finally, we aim to study the molecular signaling pathway changes within the glomerulus during disease progression with specific focus on GEC and to validate these data in human AS biopsies (Aim 2). Successful completion of this proposal will provide novel insights into the key factors critical for maintenance of glomerular structure and function. Importantly, this knowledge would likely be applicable to other forms of CKD and possibly will facilitate the discovery of new therapeutic agents tailored specifically to minimize glomerular damage.


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 = $525,260 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/18/2023	NON-COMPETING CONTINUATION	$525,260
														Subtotal = $525,260

Issue Date FY: 2022 ( Subtotal = $525,260 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/31/2022	NON-COMPETING CONTINUATION	$52,527
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/11/2022	NON-COMPETING CONTINUATION	$472,733
														Subtotal = $525,260

Issue Date FY: 2021 ( Subtotal = $541,893 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/9/2021	NON-COMPETING CONTINUATION	$541,893
														Subtotal = $541,893

Issue Date FY: 2020 ( Subtotal = $570,751 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/31/2020	NEW	$570,751
														Subtotal = $570,751

Grand Total All Awards = $2,163,164

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Extracellular vesicles derived from amniotic fluid stem cells normalize glomerular function during progressive kidney disease.

Award Number: R01DK121037

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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