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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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Summary The GnRH-1 neurons are cells in the brain that control pubertal onset, sexual competence and fertility of vertebrates. During development, the GnRH-1 neurons migrate from the embryonic nasal area into the brain, where they will eventually take up positions in the hypothalamus to control the release of gonadotropins from the pituitary gland. Defects in GnRH-1 migration induce various types of hypogonadotropic hypogonadism (HH) in humans, characterized by delayed pubertal onset, hypogonadism, and infertility. HH in humans manifests clinically as either Kallmann syndrome (KS) or normosmic idiopathic HH (nIHH). In KS, nIHH is associated with deficiencies in the sense of smell. This association led to the long-held, prevailing view that the GnRH-1 neurons migrate from the nose to the hypothalamus along the axons of olfactory and vomeronasal sensory neurons. However, we still do not know whether his assumption of GnRH-1 migration patterns is true. The overall objective of this application is to delineate the molecular mechanisms that guide GnRH-1 neurons and their migratory scaffold. Our central hypothesis states that GnRH-1 neurons migrate to the hypothalamus on the Terminal Nerve (TN), whose development occurs through molecular signals that only partially overlap with those controlling olfactory and vomeronasal neuronal development. The rationale for this hypothesis derives from understanding how specific genetic mutations linked to KS and nIHH can negatively affect TN development and induce GnRH-1 neuron mispositioning, independent from the olfactory system development. Our preliminary data indicate that transcriptional activator/repressor of the sonic hedgehog signaling pathway, Gli3, controls TN developments and GnRH-1 migration to the brain. Guided by our strong preliminary data, we will test our hypothesis through two specific aims: 1) Determine how the transcriptional regulator Gli3 regulates TN development and GnRH-1 neuronal migration and 2) Define the biologic role of GLI3 mutations in the etiology of KS/nIHH in humans. Our approach is innovative. We will exploit mouse genetics, advanced imaging techniques, human whole genome sequencing data and complementary in-vitro and in-vivo experiments to discover new mechanisms underlying TN development and formation of a functional GnRH-1 system in vertebrates. The proposed research is significant, since it will advance and expand vital clinical information for KS and nIHH 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: 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 = $1,163,165

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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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