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Understanding the role of the transcription factor Gli3 in Kallmann syndrome and normosmic forms of idiopathic hypogonadotropic hypogonadism

Award Number: R01HD097331
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Puberty is a transformative developmental process resulting in sexual and reproductive maturity. Both the onset of puberty and fertility in adult life depend on the activity of neurons expressing gonadotropin-releasing hormone- 1 (hereafter referred to as GnRH-1ns). Originating in the nasal placode during embryonic development, GnRH- 1ns migrate along axons to the hypothalamus, where they take up residence in the brain and regulate the release of gonadotropins from the pituitary gland throughout life. Defective GnRH-1 neuronal development can cause congenital hypogonadotropic hypogonadism (HH), and sex hormone deficiencies that can cause delays or the absence of puberty, resulting in infertility. HH can manifest clinically as either (i) Kallmann syndrome (KS), wherein HH is associated with different levels of olfactory deficits, or (ii) normosmic idiopathic hypogonadotropic hypogonadism (nIHH), wherein HH occurs with a normal sense of smell. The migration of GnRH-1ns proceeds along the axons of the terminal nerve and is known to depend on an additional cell type, the olfactory ensheathing cells (OECs). However, what cellular and molecular mechanisms underlie the development of the olfactory ensheathing cells, and the terminal nerve of mammals is still largely unknown. The long-term goal of our research program is to discover the molecular mechanisms leading to Kallmann syndrome and normosmic forms of niHH. By screening a cohort of human patients, we recently discovered that a loss-of-function mutation in the gene encoding the transcriptional regulator Gli3 was associated with KS. Moreover, our preliminary data show that Gli3 loss-of-function affects both OECs and terminal nerve development in mice. Our central hypothesis states that Gli3 controls the development of the terminal nerve and the development of the OECs in a dose-dependent fashion. Moreover, we postulate that and that the expression of inductive factors in the developing olfactory system controls the formation of the OECs. Guided by our strong preliminary data, we will here test our hypothesis through three specific aims: 1) To determine the dose- dependent effects of Gli3 on terminal nerve development and gene expression. 2) To identify Gli3 gene targets in the developing nose. 3) To discover the molecular mechanisms controlling the development of OECs. Our innovative approach will exploit advanced single-cell transcriptomics, mouse genetics, imaging, CUT&RUN, and bioinformatics to discover mechanisms underlying the development of the terminal nerve and OECs and the formation of a functional GnRH-1 system. The proposed research is significant to human health since it will advance and expand our understanding of KS and nIHH disease mechanisms in humans. The results from these studies will improve diagnostic criteria and stimulate the development of novel treatments and therapeutic strategies to improve the human condition.


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 = $328,236 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	001	6	7/23/2024	COMPETING CONTINUATION	$328,236
2024	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	5	7/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $328,236

Issue Date FY: 2023 ( Subtotal = $229,763 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	5	2/22/2023	NON-COMPETING CONTINUATION	$229,763
														Subtotal = $229,763

Issue Date FY: 2022 ( Subtotal = $229,772 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	4	2/10/2022	NON-COMPETING CONTINUATION	$206,794
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	001	4	4/20/2022	NON-COMPETING CONTINUATION	$22,978
														Subtotal = $229,772

Issue Date FY: 2021 ( Subtotal = $228,849 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	3	2/17/2021	NON-COMPETING CONTINUATION	$228,849
														Subtotal = $228,849

Issue Date FY: 2020 ( Subtotal = $234,285 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	2	2/21/2020	NON-COMPETING CONTINUATION	$234,285
														Subtotal = $234,285

Issue Date FY: 2019 ( Subtotal = $240,496 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Child Health and Human Development Extramural Research	000	1	3/12/2019	NEW	$240,496
														Subtotal = $240,496

Grand Total All Awards = $1,491,401

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Understanding the role of the transcription factor Gli3 in Kallmann syndrome and normosmic forms of idiopathic hypogonadotropic hypogonadism

Award Number: R01HD097331

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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