2006 — 2009 |
Pepling, Melissa |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Regulation of Oocyte Development
Melissa Pepling Proposal # 0613895 Regulation of Oocyte Develpment
In mammals, the final number of eggs, or oocytes, available for reproduction of the next generation is defined at birth. Establishment of this oocyte pool is essential for fertility. Mouse oocytes develop in clusters of cells that break apart into individual cells and become packaged into primordial follicles within a few days of birth. During this time only a subset of eggs ultimately survive. The remaining immature eggs die by a normal developmental process called programmed cell death. This phase of oocyte differentiation is poorly understood and molecules and mechanisms that regulate this stage of oocyte development have not been identified. Recently, estrogen treatment of neonatal mice was found to alter oocyte development by inhibiting the oocyte clusters from breaking apart and protecting cells from death suggesting that estrogen signaling may regulate egg development. The goal of the research described in this proposal is to understand the role of estrogen signaling in normal oocyte development. First, the way in which estrogen signals to oocytes will be examined using estrogen related compounds and mice lacking estrogen receptors. Second, the role of estrogen signaling in programmed cell death regulation will be explored using genetics and cell death inhibitors. Finally, target genes of estrogen signaling will be identified. Information from this work will aid in understanding normal oocyte differentiation. It will also contribute better understanding of mammalian infertility and ovarian cancer. In addition to its impact on developmental biology, the project will foster the education and training of future scientists through active participation of both undergraduate and graduate students.
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1 |
2012 — 2016 |
Pepling, Melissa |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Estrogen Signaling in Oocyte Development
Despite its importance to the continuation of species, the differentiation of primordial germ cells into functional oocytes is poorly understood. Primordial germ cells begin to differentiate into oocytes during embryonic development in the mouse. The oocytes develop in clusters called germline cysts, a conserved phase of oocyte development in both vertebrates and invertebrates. During late fetal and early neonatal development, mouse germ cell cysts break apart into single oocytes (cyst breakdown) that become surrounded by pre-granulosa cells to form primordial follicles (follicle formation). During the process of cyst breakdown, a subset of cells in each cyst die with only a third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control cyst breakdown, oocyte survival and follicle assembly are currently unknown. However, recent work suggests estrogen signaling may play an important role in maintaining oocytes in cysts. The project goal is to understand the role of estrogen signaling in cyst breakdown and primordial follicle formation. Establishing the role of estrogen signaling in neonatal oocyte differentiation will elucidate mechanisms leading to formation of the primordial follicle pool. This work will to contribute to our knowledge of conserved mechanisms of germ cell differentiation and lead to a better understanding of mammalian infertility. In addition to its impact on ovarian function, the project will foster education and training through active participation of both undergraduate and graduate students. Community outreach will be achieved by revival of a program that brings together scientists and nonscientists in the community and by participation in a local science program for high school girls.
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1 |
2015 |
Pepling, Melissa E |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Regulation of Primordial Follicle Formation and Oocyte Survival
? DESCRIPTION (provided by applicant): Despite its importance to the continuation of species, the differentiation of primordial germ cells into functional oocytes is poorly understood. Primordial germ cells begin to differentiate into oocytes during embryonic development in the mouse. Prior to birth, the oocytes develop in clusters called germline cysts, a conserved phase of oocyte development in both vertebrates and invertebrates. During late fetal and early neonatal development, mouse germ cell cysts break apart into single oocytes that become surrounded by pre-granulosa cells to form primordial follicles. During this process of cyst breakdown, a subset of cells in each cyst die with only a third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control cyst breakdown, oocyte apoptosis and follicle assembly are currently unknown. The long-term goal is to understand molecular and cellular mechanisms that regulate cyst breakdown and programmed cell death to establish the primordial follicle pool in the mouse ovary. The objective of this proposal is to determine the role of two pathways, the KIT signaling pathway and the BCL2 apoptotic pathway in modulating cyst breakdown and oocyte numbers. The central hypothesis of the proposed research is that cyst breakdown and germ cell death are controlled by signaling through the receptor tyrosine kinase, KIT and by a balance of BCL2 pro- and anti-apoptotic proteins. Recent work from our laboratory suggests KIT signaling may play an important role. In addition, we provide preliminary data demonstrating that BCL2 family proteins are also important for the regulation of cyst breakdown and associated programmed cell death. This proposal explores the molecular and cellular aspects of KIT signaling and programmed cell death regulators in cyst breakdown and oocyte survival. The specific aims of this research are to: 1) elucidate the molecular and cellular mechanisms of KIT signaling in cyst breakdown and associated oocyte loss; and 2) identify BCL2 family members involved in regulating oocyte survival. These goals will be achieved through techniques including immunocytochemistry, confocal microscopy, Western blotting, ovary organ culture, pharmacological inhibitors, siRNA technology and genetics. Research proposed in the current application is significant because it will enhance our current knowledge by elucidating the mechanisms by which cyst breakdown and associated oocyte loss are regulated. Results obtained in this grant will help improve research efforts in ovarian biology and in treatment of conditions causing female infertility such as primary ovarian insufficiency.
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0.958 |
2019 |
Pepling, Melissa E |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Regulation of Oocyte Development by Steroid Hormones
Despite its importance to the continuation of species, the differentiation of primordial germ cells into functional oocytes is poorly understood. Primordial germ cells begin to differentiate into oocytes during embryonic development in the mouse. The oocytes develop in clusters called germline cysts, a conserved phase of oocyte development in both vertebrates and invertebrates. Oocytes progress through prophase I of meiosis and arrest at the diplotene stage. They then undergo primordial follicle formation during which germ cell cysts break apart into single oocytes (cyst breakdown) and granulosa cells migrate around individual oocytes to form primordial follicles. During the process of cyst breakdown, a subset of cells in each cyst die with only a third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control meiotic progression, cyst breakdown, granulosa cell recruitment and oocyte survival are not well understood. The long-term goal is to understand molecular and cellular mechanisms that regulate cyst breakdown and programmed cell death to establish the primordial follicle pool in the mouse ovary. The objective of this proposal is to understand the role of steroid hormone signaling in regulating primordial follicle formation. The central hypothesis of the proposed research is that steroid hormone signaling maintains oocytes in cysts and prevents premature progression to the diplotene stage. Work from our lab suggests steroid hormone signaling may play an important role in maintaining oocytes in cysts and controlling meiotic progression. The specific aims of this research are to: 1) elucidate the source and molecular mechanisms of steroid hormone signaling in regulation of primordial follicle formation; and 2) identify targets downstream of steroid hormone signaling during oocyte development. These goals will be achieved through a variety of methods including immunohistochemistry, confocal microscopy, ovary organ culture, genetics, real time PCR and next generation sequencing. Research proposed in the current application is significant because it will enhance our current knowledge by elucidating the mechanisms by which cyst breakdown and associated oocyte loss are regulated. Results obtained in this grant will help improve research efforts in ovarian biology and in treatment of conditions causing female infertility such as primary ovarian insufficiency.
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0.958 |