Area:
Human Development, Cell Biology, Pharmacology
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High-probability grants
According to our matching algorithm, Patricia A. Labosky is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
1999 — 2003 |
Labosky, Patricia A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Analysis of Winged Helix Genes in Development of the Cns @ University of Pennsylvania
Mammals are unique among vertebrates because they feed their young with specialized mammary glands. The ability to lactate is necessary for the survival of most non-human mammals and is highly desirable for the health and well-being of human infants. Approximately 40 percent of women in Western cultures have lactation defects that are extremely painful and often result in the cessation of breastfeeding. We have previously generated mice carrying a mutation in the winged helix transcription factor Mf3. Members of this gene family play important roles during embryonic development and postnatal homeostasis. The resulting lactation defect in the Mf3 -/- females is an ideal model to study general mechanisms of tissue differentiation, axonal circuitry and neural control. To determine the cellular basis of the Mf3 -/- defect we have insetted a lineage marker into the Mf3 locus to follow the fate of Mf3 expressing cells in the CNS and mammary glands. These experiments will test the following two hypotheses: Mf3 expression is necessary for proper axonal connections between the thalamus and hypothalamus, and Mf3 -/- females have defects in the axonal circuitry resulting in disruption of the milk-ejection reflex and Mf3 expression in the mammary glands is necessary for the normal development of mammary glands in utero and/or after puberty. Lactation is initiated by afferent stimuli of the young suckling at the nipple. This stimulus is transmitted via the spinal cord to the hypothalamus where oxytocin is released. Oxytocin acts on myoepithelial cells of the mammary gland causing them to contract and eject milk. Mf3 is expressed in restricted regions of the CNS and in developing mammary glands. Using the Cre-loxP system we will selectively mutate the Mf3 gene in the CNS to test the following hypothesis: The CNS expression of Mf3 is critical for the normal milk-ejection response. We will also delete Mf3 expression in mammary glands to test the following two hypotheses: 1. The ability to lactate normally is dependent on a functioning mammary gland and the embryonic expression of Mf3 is necessary for normal differentiation of the mammary gland. 2. The adult expression of Mf3 in the mammary gland is essential so the afferent suckling stimulus is transmitted via the spinal cord to the hypothalamus, oxytocin is released and milk is ejected. This model provides an important experimental paradigm to study general mechanisms of developmental regulation.
|
0.948 |
2004 — 2009 |
Labosky, Patricia A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Crest Formation and Maintenance of Multipotency @ University of Pennsylvania
DESCRIPTION (provided by applicant): The neural crest is a multipotent population of embryonic cells with the ability to contribute to a variety of adult derivatives: neural, endocrine, pigment, and mesenchymal. Because neural crest cells have this intrinsic multipotency, they represent a system in which to explore molecular requirements of multipotent stem cells. Stem cells are a unique tissue with the potential for disease therapy and cell transplantation. However, in order to take advantage of these biological possibilities, we must understand the genetic pathways involved, identify stem cell progenitors prospectively and control their maintenance and differentiation. We have identified a transcription factor, Foxd3 that is sufficient to specify neural crest. Foxd3 is required for normal murine development and the establishment of two embryo-derived stem cell lineages: embryonic stem (ES) cells and trophoblast stem (TS) cells. Aim 1 tests the requirement for Foxd3 in vivo to specify and/or maintain neural crest cells. Adult progenitor cells reside in specialized niches and are recruited to renew or repair tissue thereby maintaining homeostasis. Multipotent neural crest stem cells (NCSCs) can be isolated from both embryonic neural crest cells and some postnatal neural crest derivatives. Foxd3 is expressed in NCSCs and in scattered cells of the adult nervous system known to contain progenitor cells. Experiments in Aim 2 will determine the identity of Foxd3 expressing cells in the adult and if these cells are residing in a stem cell niche. Because Foxd3 is required in other stem cell populations, experiments in Aim 3 will determine if Foxd3 plays a role in the establishment and maintenance of postnatally derived neural crest stem cells (NCSCs). These experiments are all linked to the same biological process of establishing and/or maintaining multipotent cell properties in stem cells from different sources. Understanding the molecular regulation of common properties of different stem cell types is critical to understanding how these cells can maintain multipotency as well as how their differentiation might be controlled in vitro and potentially in vivo.
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1 |