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Integrating signals that control APOL1 gene expression and drive kidney disease

Award Number: R01DK138503
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2012
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Integrating signals that control APOL1 gene expression and drive kidney disease - SUMMARY: Two ancestry-associated coding variants in APOL1 drive much of the racial disparity in rates of kidney disease. However, the presence of two risk alleles (a high-risk genotype) does not lead to kidney disease in all or even most individuals, indicating that other factors must also be important. Several environmental 2nd hits have been identified such as HIV, therapeutic interferon, and Covid19. APOL1 itself is an innate immune factor induced by interferons. A unifying theme is that both the APOL1 high-risk genotype and factors that elevate APOL1 expression are required for development of APOL1 kidney disease. In addition to APOL1 protein function as a membrane pore, APOL1 mRNA 3’-UTR has inversely oriented alu repeats that form a hairpin loop of double- stranded RNA (dsRNA). This loop acts as an inflammatory factor because dsRNA is recognized by pattern recognition receptors (PRR). Activation of PRR induces an anti-viral state with production of additional interferons, which can trigger more APOL1 expression in a vicious cycle. Several mechanisms act as brakes on APOL1 activity to prevent excess toxicity including transcript repression by miRNA and prevention of the PRR inflammatory response by the A-to-I editing enzyme ADAR. We believe that imbalance between APOL1 activation and suppression may trigger kidney disease. To continue these studies, we will now: (1) Examine how miRNA activity at the APOL1 3-’UTR regulates APOL1 expression. miRNA regulate gene expression by binding to mRNA (usually 3’-UTR), promoting its degradation. We identified ~80 miRNAs in a high-throughput screen with the potential to reduce APOL1 mRNA levels. We will perform a counterscreen to identify the most potent miRNA at preventing APOL1 upregulation by interferons. We will find the intersection between miRNA expressed in the podocyte and those that repress APOL1. We will test whether human polymorphisms in the APOL1 3’- UTR alter miRNA binding and gene expression. We will validate the most relevant miRNA in vivo in APOL1 BAC transgenic mice. (2) Characterize environmental and endogenous factors that induce or modify APOL1 expression. We will test a wide range of exogenous and endogenous molecules for their ability to induce APOL1 expression and to modulate cytokine-driven APOL1 expression. We will test the most potent molecules in APOL1 BAC transgenic mice. (3) Examine the role of APOL1 mRNA as an innate immune signaling molecule. We will determine the specific PRR that recognize APOL1 3’-UTR dsRNA and whether that recognition and the resulting inflammation depends on APOL1 genotype. We will assess how A-to-I editing of the APOL1 3’-UTR by ADAR or protection by mRNA binding proteins may prevent the inflammatory loop driven by PRR recognition of APOL1 mRNA. We will test the effect of ADAR editing on the stability of the APOL1 mRNA and how A-to-I editing alters 3’-UTR binding by miRNA. Together, these experiments will help us understand the positive and negative factors that regulate the interferon-driven APOL1 feed-forward inflammatory loop, APOL1 expression levels, and podocyte injury leading to kidney disease.


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 = $486,269 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	1/8/2025	NON-COMPETING CONTINUATION	$486,269
														Subtotal = $486,269

Issue Date FY: 2024 ( Subtotal = $540,299 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$540,299
														Subtotal = $540,299

Grand Total All Awards = $1,026,568

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Integrating signals that control APOL1 gene expression and drive kidney disease

Award Number: R01DK138503

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2012

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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