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An ovary-on-a-chip for understanding early folliculogenesis and reproductive toxicology in a large mammalian model

Award Number: F32HD090854
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY/ABSTRACT Recapitulation of folliculogenesis in vitro is of interest for both preserving human fertility and assessing the influence of chemical contaminants on ovarian health. Although live offspring can be produced from oocytes recovered from murine follicles grown in vitro, the larger size and protracted duration of folliculogenesis of large mammals likely necessitates more complex culture requirements. The domestic cat will be used as a study model because this species shares a number of anatomical and reproductive characteristics including follicle size and oocyte nuclear configuration with the human. The proposed project will take advantage of ‘organ-on-chip’ microfluidic technology combined with somatic cell co-culture and my experience with 3-dimensional hydrogels to recapitulate, as possible, in vivo conditions in an “ovary-on-a-chip”. Specifically, I propose to quantify the rigidity of the domestic cat ovary via micropipette aspiration and atomic force microscopy and identify biomimetic densities of alginate hydrogel that provide optimal structural support to primordial follicles. I will determine the influence of rigidity and medium flow rate on in vitro folliculogenesis, and identify via tandem mass spectrometry and RNA sequencing technologies, proteins and genes involved in follicle activation in culture. Comparison of the dynamic system with traditional, static culture will allow me to improve understanding of the contributions of structural rigidity (hydrogel density), medium flow (microfluidic chip), and the paracrine environment (produced via co-culture) on follicle survival and activation in vitro (Aim 1). I then propose to evaluate the epigenetic impacts (methylation of histones, key imprinted genes) of long-term culture in this system compared with traditional culture, as well as determine the utility of the “ovary-on-a-chip” in ovarian toxicology studies, using the active form of the chemotherapeutic cyclophosphamide in proof-of-concept studies (Aim 2). Together, these studies advance understanding of contributions of the microenvironment on follicle development toward the goal of an in vitro system for enhancing fertility preservation and reproductive toxicology.


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 = $0 )
2023	2020	SMITHSONIAN INSTITUTION	1000 JEFFERSON DR SW	WASHINGTON	DC	20560	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	001	4	1/19/2023	NON-COMPETING CONTINUATION	$0
2023	2019	SMITHSONIAN INSTITUTION	1000 JEFFERSON DR SW	WASHINGTON	DC	20560	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	2	1/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $112,456 )
2020	2020	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	000	3	11/2/2019	NON-COMPETING CONTINUATION	$64,606
2020	2020	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	002	3	3/2/2020	NON-COMPETING CONTINUATION	$4,700
2020	2020	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	004	3	9/21/2020	NON-COMPETING CONTINUATION	$0
2020	2020	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	005	4	9/22/2020	NON-COMPETING CONTINUATION	$40,578
2020	2020	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	003	3	7/28/2020	NON-COMPETING CONTINUATION	$0
2020	2019	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	001	2	2/27/2020	NON-COMPETING CONTINUATION	$2,572
														Subtotal = $112,456

Issue Date FY: 2019 ( Subtotal = $61,174 )
2019	2019	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	000	2	10/25/2018	NON-COMPETING CONTINUATION	$61,174
														Subtotal = $61,174

Issue Date FY: 2017 ( Subtotal = $57,066 )
2017	2017	SMITHSONIAN INSTITUTION	2011 CRYSTAL DR STE 352	ARLINGTON	VA	22202	ARLINGTON	USA	Child Health and Human Development Extramural Research	000	1	7/31/2017	NEW	$57,066
														Subtotal = $57,066

Grand Total All Awards = $230,696

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An ovary-on-a-chip for understanding early folliculogenesis and reproductive toxicology in a large mammalian model

Award Number: F32HD090854

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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