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Interaction of Galectin-9 and Pregnancy-Specific Glycoprotein 1 in the Regulation of Cells of the Innate and Adaptive Immune System

Award Number: R21AI156058
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT The importance of placental and decidual secreted factors as mediators of the immunological adjustments needed to accommodate the genetically different mother and fetus during hemochorial pregnancies is well recognized. Galectins are a family of lectins with intracellular and extracellular functions. Secreted galectins bind to N-acetyllactosamine (LacNAc) and form lattices between glycoproteins on the surface of cells and between cells, promoting a plethora of biological activities including regulation of the adaptive and innate immune response. Members of the galectin family exhibit notable differences in carbohydrate specificity and affinity resulting in different functions. Recently, Galectin-9 (Gal-9), which is expressed at the maternal fetal- interface, has been suggested to play a role in maternal T-cell tolerance by binding to its receptors which include among others T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and CD44. On the other hand, Gal-9 has been reported to induce the secretion of pro-inflammatory cytokines by myeloid cells. Recently, we found that Pregnancy-specific glycoprotein 1(PSG1), which is secreted by placental trophoblasts at increasing concentration as pregnancy progresses, binds to Gal-9. PSG1 binds to Gal-9 with high affinity and the interaction is glycan-mediated. Importantly, the concentration of PSG1 is lower than normal in some pregnancy complications including pre-eclampsia. Activation of the innate immune system has been proposed to contribute to trophoblast invasion in the early decidua and to parturition, however it is also associated with adverse pregnancy outcomes when it occurs in the second and third trimesters. Therefore, the temporal and spatial aspects of reducing inflammation during pregnancy represent a complex and essential process for pregnancy success. We propose that the newly found interaction between Gal-9 and PSG1 contributes to the qualitative differences in the immune response required for pregnancy success and that besides their previously identified individual functions, the interplay between these two proteins plays an important role in the modulation of immune cells. Therefore we propose to carry out the following Specific Aims: (1) Analyze the binding of native and recombinant PSG1 to the N-terminal and C-terminal carbohydrate recognition domains of Gal-9. (2) Determine the individual and combined effects of PSG1 and Gal-9 or the individual Gal-9 CRDs on the phenotype and secretion of cytokines by monocytes and decidual macrophages. (3) Determine the effect of individual and combined treatment of PSG1 and Gal-9 in human CD4+ T-cell apoptosis and frequency of CD4+ FoxP3+ T-regulatory cells.


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: 2024 ( Subtotal = $0 )
2024	2022	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $228,744 )
2022	2022	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	5/31/2022	NON-COMPETING CONTINUATION	$228,744
														Subtotal = $228,744

Issue Date FY: 2021 ( Subtotal = $190,621 )
2021	2021	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	6/18/2021	NEW	$190,621
														Subtotal = $190,621

Grand Total All Awards = $419,365

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Interaction of Galectin-9 and Pregnancy-Specific Glycoprotein 1 in the Regulation of Cells of the Innate and Adaptive Immune System

Award Number: R21AI156058

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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