Area:
Endocrinology, GnRH Receptor
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High-probability grants
According to our matching algorithm, Amy M. Navratil is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2009 — 2010 |
Navratil, Amy M. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
The Role of Erk in Pituitary Organogenesis
DESCRIPTION (provided by applicant): Long Term Objective: To define the role of ERK in pituitary development Aim 1. What is the requirement for ERK signaling during pituitary organogenesis? The working hypothesis underlying Aim 1 is that ERK signaling is necessary for anterior pituitary proliferation and/or cell lineage commitments. Aim 1 seeks to examine the in vivo role of ERKs on pituitary organogenesis using two separate models for Cre recombinase-mediated ERK gene deletion. We will focus on comparing an early global ERK knockout using the Pitxl Cre-expressing mouse line with an aGSU-CRE model where ERK deletion is lineage restricted to establish the role of ERK signaling during pituitary development. These studies include an analysis of histopathology, cell proliferation, survival and a complete assessment of lineage specification using immunohistochemistry for markers of lineage identity during pituitary development. These studies will, for the first time, define the requirement(s) for ERK signaling necessary for pituitary development and endocrine cell lineage commitment during pituitary organogenesis and set the framework for Aim 2 examining potential mechanisms of ERK signaling throughout the developing pituitary. Aim 2. What is the mechanistic relationship between onset of FGF signaling, activation state of ERKs, and downstream transcriptional responses during pituitary development? The hypothesis underlying Aim 2 is that ERK is activated in response to FGF signaling within the developing pituitary. Our preliminary studies provide compelling evidence that ERK activities are spatially and temporally regulated during development potentially correlated with FGF signaling gradients during Rathke's pouch formation. To directly test this, Aim 2 seeks to clarify the activity state of ERKs during organogenesis in an FGF KO mouse model. Next, we will establish the relationship between ERK and the well characterized downstream transcriptional networks that are crucial for pituitary development in our ERK KO mouse models. Initially, we will focus on immunohistochemical analysis the LIM homeodomain transcription factors, Lhx3 and lsl-1. Defining the role of ERK in pituitary development will lead to a broader understanding of the mechanisms involved in various dysfunctional pituitary conditions such as, CPHD and infertility.
|
0.957 |
2017 — 2018 |
Cherrington, Brian D. [⬀] Navratil, Amy M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
The Role of Citrullination in Gonadotrope Function
Gonadotropin Releasing Hormone (GnRH) stimulates peptidylarginine deiminase (PAD) catalyzed citrullination of histones and cytoskeletal filaments in gonadotropes, yet the physiological consequence of this on reproductive function is lacking. This gap in knowledge is an important problem because proper gonadotrope function is critical for all vertebrate reproduction and a major therapeutic target for infertility and contraception. Our long-term goal is to develop a detailed understanding of the molecular targets of citrullination and its physiological implications in gonadotropes. The objective of this proposal is to identify citrullination as a novel regulator of gonadotrope specific gene programs and cytoskeletal function in vivo. Our published data demonstrates that GnRH induces PAD catalyzed citrullination of arginine residues on histones to regulate expression of the luteinizing hormone (LH) ? subunit gene. Preliminary RNA-seq data suggests that citrullination also regulates the of expression endoplasmic reticulum processing and golgi vesicle trafficking gene networks not previously characterized in gonadotropes. In addition to histones, our data shows that PADs citrullinate ?-tubulin and ?-actin to regulate cytoskeletal reorganization following GnRH stimulation. Our central hypothesis is that GnRH utilizes PAD catalyzed citrullination of histones and cytoskeletal proteins to implement critical molecular changes necessary for LH synthesis, spatial repositioning of cells, and effective hormone secretion. The central hypothesis will be tested with the following specific aims: (1) To test whether genes governing gonadotropin synthesis and processing are regulated by GnRH induced PAD catalyzed histone citrullination in vitro and in vivo. (2) To identify citrullinated cytoskeletal filaments and determine how these modifications regulate gonadotrope function. In Aim 1, the expression of target genes identified by RNA-seq in L?T2 gonadotropes will be examined following GnRH and PAD inhibitor treatment using chromatin immunoprecipitation (ChIP). Target genes will next be examined in gonadotropes purified by fluorescence activated cell sorting (FACS) from GRIC-GFP mice. Primary gonadotropes will be treated with GnRH and PAD inhibitor and target genes examined by qPCR and ChIP. Proposed studies in Aim 2 will identify citrullinated proteins from L?T2 and primary gonadotropes using a proteomic approach. The physiologic importance of citrullination on cellular architecture and LH secretion will be examined in primary gonadotropes following treatment with GnRH and a PAD inhibitor. The proposed research is innovative because we plan to determine how GnRH acting through the unexplored mechanism of citrullination can temporally initiate an epigenetic event and cytoskeletal reorganization to control gonadotrope physiology, which represents a new and substantial departure from current studies in the gonadotrope field. The work is significant because it is an important step to characterize a completely novel, unexplored mechanism stimulated by GnRH that is critical for gonadotrope function.
|
0.948 |