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The Role of Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in an animal model of polycystic ovary syndrome

Award Number: R01HD114701
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: 08/19/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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The Role of Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in an animal model of polycystic ovary syndrome - Polycystic ovary syndrome (PCOS) is a leading cause of female infertility worldwide. The syndrome is diagnosed by ovarian symptoms, including cystic ovaries, disrupted or absent menstrual cycles and hyperandrogenism. However, changes in the brain play a significant role in the development of PCOS. Under normal conditions, neurons in the hypothalamus release gonadotropin-releasing hormone (GnRH) in a pulsatile manner to elicit the secretion of luteinizing hormone (LH) from the pituitary gland. LH pulses act at the ovary to control folliculogenesis and steroid hormone release. Ovarian steroid hormones, in turn, act back in the brain through an afferent network to suppress GnRH secretion in a homeostatic negative feedback loop. In women with PCOS, the ability of steroid hormones to suppress the frequency of pulsatile GnRH/LH secretion is impaired, leading to ovarian dysfunction. The neuronal population with a diminished response to steroid hormone feedback is currently unknown. However, cells that express Kisspeptin, Neurokinin B, and Dynorphin peptides, termed KNDy cells, are a promising candidate as they are hypothesized to play a role in steroid hormone feedback and demonstrate synchronized episodes of activity that generate GnRH/LH pulses. Our recent research using a mouse model of PCOS induced using prenatal androgen (PNA) exposure demonstrated that KNDy cells have lower expression of receptors required for steroid hormone feedback and a significant reduction in synaptic innervation by GABAergic afferent networks. Based on these findings, we hypothesize that increased GnRH/LH pulse frequency in PCOS is mediated by changes in the regulation of KNDy cells by steroid hormones and afferent networks. To investigate this, our first aim will use in vivo calcium imaging, which permits the visualization of individual cell activity within a population of neurons in freely behaving mice, to define if increased LH pulse frequency in PNA mice is associated with an impaired ability of estradiol and progesterone to suppress KNDy cell activity. Our second aim will identify the origin of reduced GABAergic afferent input to KNDy cells using retrograde monosynaptic rabies-mediated tract tracing. We will then define how a loss in GABAergic afferent input functionally impacts KNDy cell activity by combining in vivo calcium imaging of KNDy cells in fertile mice whilst optogenetically manipulating the activity of apposing GABAergic axon terminals. Finally, we will use chronic chemogenetic inhibition of KNDy cells to determine if exogenously regulating KNDy cell-mediated GnRH/LH pulse generation is sufficient to override neuroendocrine dysfunction in PNA mice and restore reproductive capacity. Together, this research will greatly improve our understanding of how GnRH pulse generation is regulated, both in individuals who are healthy and in those who develop PCOS. As there are ongoing clinical studies aiming to reduce synchronized KNDy cell activity in PCOS patients, such as through the use of pharmaceutical antagonists against the neurokinin B receptor, this research may offer valuable information to guide the development of treatments targeting central dysfunction in the syndrome.


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: 2026 ( Subtotal = $326,800 )
2026	2026	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	3	5/19/2026	NON-COMPETING CONTINUATION	$326,800
														Subtotal = $326,800

Issue Date FY: 2025 ( Subtotal = $326,800 )
2025	2025	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	2	4/22/2025	NON-COMPETING CONTINUATION	$326,800
														Subtotal = $326,800

Issue Date FY: 2024 ( Subtotal = $326,800 )
2024	2024	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	1	8/19/2024	NEW	$326,800
														Subtotal = $326,800

Grand Total All Awards = $980,400

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The Role of Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in an animal model of polycystic ovary syndrome

Award Number: R01HD114701

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: 08/19/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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