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Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex

Award Number: R01DK133243
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: 04/05/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex - Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline loss-of-function mutations in the TSC1 or TSC2 gene. Renal disease, which includes angiomyolipomas, cysts, and carcinomas, is the second leading cause of morbidity and mortality in TSC. In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human TSC renal cysts and angiomyolipomas. We also demonstrate that B7-H3 promotes TSC2-null cell growth in vivo via a mechanism that requires CD8+ T cells. These and other data lead to our central hypothesis: immunosuppressive macrophages together with B7-H3 expression on TSC2-deficient cells promote renal disease in TSC. A key translational corollary of this hypothesis is that immunosuppressive macrophages and B7-H3 are potential therapeutic targets for TSC. Aim 1: To identify the mechanisms through which macrophages contribute to the renal manifestations of TSC. We will test the hypothesis that immunosuppressive macrophages promote TSC1- and TSC2-deficient cell growth directly, and/or indirectly via inhibition of CD8+ T cell function. Aim 2: To determine how B7-H3 remodels the immune microenvironment of TSC-associated renal disease. We will test the hypothesis that B7-H3 promotes TSC2-null cell growth by inhibiting CD8+ T cell function. Aim 3: To investigate the preclinical efficacy of co-targeting macrophages and B7-H3 in TSC. We will test the hypothesis that targeting both immunosuppressive macrophages and B7-H3 will lead to long-lasting, durable responses in preclinical models of renal disease driven by loss of Tsc1 or Tsc2. We expect this project to have scientific impact by identifying the immune mechanisms responsible for the growth of TSC2-null cells in the kidney. These mechanisms may have broad implications, since macrophages are believed to play a key role in other renal diseases, including autosomal dominant polycystic kidney disease (ADPKD). Our areas of innovation include our novel, translationally relevant hypotheses as well as technical innovation, including CITE-seq, spatial CODEX and nanoString transcriptomic profiling, and a novel, unpublished mouse model of renal disease in TSC (Rosa26-CreERT2 Tsc2f/f).


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 = $523,592 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/24/2025	NON-COMPETING CONTINUATION	$523,592
														Subtotal = $523,592

Issue Date FY: 2024 ( Subtotal = $506,772 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/3/2024	NON-COMPETING CONTINUATION	$506,772
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/31/2024	NEW	$0
														Subtotal = $506,772

Issue Date FY: 2023 ( Subtotal = $539,046 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/3/2023	NEW	$539,046
														Subtotal = $539,046

Grand Total All Awards = $1,569,410

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Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex

Award Number: R01DK133243

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: 04/05/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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