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Maternal Central Immune Tolerance in Reproduction

Award Number: R01HD100832
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Maternal Central Immune Tolerance in Reproduction - The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mother’s immune system at the commencement and for the duration of pregnancy. When this tolerance fails, infertility, preterm birth and delivery, preeclampsia, or fetal growth restriction may result. Aire is a transcriptional regulator that induces expression of tissue-restricted genes in the thymus, wherein central tolerance to many self-antigens is acquired. Aire ensures that tolerance to such antigens is established in developing T cells. Tissue-restricted genes regulated by Aire include many that are specific to the fetus and placenta, and we have found not only that Aire is upregulated in the thymus during pregnancy, but also that global Aire deficiency can predispose dams to fetal loss. Intriguingly, our group and others have also identified Aire expression in the ovary and uterus, suggesting an additional, extrathymic role of this transcription factor. In this project, we aim to define the role of Aire in immune tolerance to the fetus, elucidate its regulation by sex hormones, and clarify its immune- independent role in reproduction. We will test the overall hypothesis that Aire is required for central immune tolerance the fetus, and that it functions in parallel within the uterus and ovary to support fertility. We propose two specific aims: Aim 1. Determine the impact of Aire deficiency on maternal immune tolerance to the fetus. Aim 2. Ascertain the functional connection between sex hormones and Aire in maternal central tolerance to the fetus. Aim 3. Identify the immune-independent function of Aire in female fertility. The results of these experiments are expected to provide highly novel insight into as-yet unexplored mechanisms of maternal tolerance to the fetal-placental unit, female fertility, and the regulation thereof by sex hormones, greatly advancing our understanding of maternal tolerance to the fetal allograft. The results will have far-reaching implications for women’s wellbeing in the fields of pregnancy, reproductive health, autoimmune disease, transplantation, and cancer immunology.


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 = $383,160 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	5	6/4/2024	NON-COMPETING CONTINUATION	$383,160
														Subtotal = $383,160

Issue Date FY: 2023 ( Subtotal = $399,553 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	4	4/27/2023	NON-COMPETING CONTINUATION	$399,553
														Subtotal = $399,553

Issue Date FY: 2022 ( Subtotal = $396,442 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	3	5/3/2022	NON-COMPETING CONTINUATION	$396,442
														Subtotal = $396,442

Issue Date FY: 2021 ( Subtotal = $393,492 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	2	4/22/2021	NON-COMPETING CONTINUATION	$393,492
														Subtotal = $393,492

Issue Date FY: 2020 ( Subtotal = $388,406 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Child Health and Human Development Extramural Research	000	1	7/13/2020	NEW	$388,406
														Subtotal = $388,406

Grand Total All Awards = $1,961,053

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Maternal Central Immune Tolerance in Reproduction

Award Number: R01HD100832

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/13/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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