2008 — 2011 |
Uribe, Rosa Anna |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
The in Vivo Function of Id2 in Retinal Proliferation and Differentiation @ University of Texas Austin
[unreadable] DESCRIPTION (provided by applicant): The construction of the nervous system is an integrated series of developmental steps, commencing with the segregation of a small group of embryonic cells fated to become neural progenitors. These neural progenitors then remain proliferative and undifferentiated until they have become committed to distinct neural cell fate. As in most neural tissue, within the vertebrate retina, the cell and molecular strategies that cells use to control these processes remain poorly understood. Even worse, most forms of cancer exhibit distinctly misregulated control over these events, and the nature underlying many human diseases are tied to perturbations in these processes. Therefore, the overarching goal of this proposal is to enhance our understanding of the intracellular mechanisms governing neuroblast proliferation, lineage commitment and differentiation within the developing vertebrate retina. This will be accomplished by utilizing the zebrafish retina to understand the role of the intrinsic factor Id2 (Inhiibitor of Differentiation) in retinal development. The specific Aims of this proposal are 1. To determine the function of Id2 during zebrafish retinogenesis, 2. To determine the molecular mechanisms underlying Id2 function in the developing zebrafish retina, and 3. To determine if Id2 is regulated by the Sonic Hedgehog Pathway (Shh). These Aims will be accomplished using Id2 loss and gain-of-function strategies in vivo in order to define the functional role of Id2 during zebrafish retinogenesis, and Shh loss and gain-of-function methods will also be used to assess if Id2 is regulated by Shh in the developing vertebrate retina. The experiments in this proposal will shed light on how the intrinsic factor Id2 regulates growth and differentiation of the vertebrate eye, and how it's function may be controlled by mitogenic properties of the Shh signaling pathway. As the formation of many human neurological, developmental and cancerous diseases are linked to disruptions in such early developmental processes as cell division, cell specialization and cell survival, the purpose of this study is to enhance our understanding of how these processes normally occur at the molecular level within the cell, and how they are controlled over developmental time. Specifically, this study will examine how these events occur in the developing retina, thereby increasing our knowledge of how the retina forms, and providing clues to the events that may be disrupted in the early stages of cancer, such as retinoblastoma, as well as neurodegenerative diseases affecting the retina. [unreadable] [unreadable] [unreadable]
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2014 — 2016 |
Uribe, Rosa A. |
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. |
Functional Analysis of Early Vagal Neural Crest and Ens Development @ California Institute of Technology
DESCRIPTION (provided by applicant): The enteric nervous system (ENS) is the most complex and largest portion of the peripheral nervous system. The ENS is comprised of a complex series of interconnected neurons and glia that control intestinal motility and regulate blood flow within the gut wall. During development, ENS arises from vagal neural crest cells that emigrate from the neural tube at caudal hindbrain levels. Upon reaching the foregut, the vagal-derived enteric neural crest cells migrate caudally along the developing gut and differentiate into enteric neurons and glial cell types. Abnormalities in migration to or along the gut or along resul in birth anomalies like Hirschsprung's Disease, in which the distal portion of the intestine is devoid of enteric neurons or glia, resulting in megacolon and chronic constipation. While much research attention has focused on the functional analysis of enteric neural crest cell migration in the gut during later phases of ENS development, the molecular mechanisms that regulate their migration and the designation of early vagal and enteric neural crest cell identity is poorly understood. The experiments in this proposal will utilize zebrafish and chicken embryos in order to enhance our understanding of the mechanisms that regulate early phases of vagal neural crest and ENS development. Both chicken and zebrafish embryos develop externally, allowing for easy experimental manipulation and observation. Furthermore, zebrafish embryos are transparent during development allowing for high-resolution analysis of neural crest cell migration. The specific aims are to 1. Investigate the role of Meis3 in development of the zebrafish enteric neural crest, and 2. Elucidate the role and regulation of Hoxb5 in vagal and enteric neural crest development. The results of these experiments will significantly improve our basic understanding of enteric neural crest cell migration and fate specification, thus providing a solid foundation on which to base upstream translational research endeavors.
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2021 |
Uribe, Rosa 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. |
Genetic and Extrinsic Mechanisms Governing Early Enteric Nervous System Development
Resident between the muscle walls of the entire gastrointestinal (GI) tract, the enteric nervous system (ENS) consists of a series of interconnected neurons and glia, numbered in the hundreds of millions. The ENS controls essential gut functions, such as peristalsis, water balance and intestinal barrier homeostasis. The ENS is derived from enteric neural progenitors (ENPs) that migrate into the developing gut tube during embryogenesis and differentiate into enteric neurons or glia. Disruption in ENS formation results in the congenital condition Hirschsprung disease (HSCR), in which variable regions of the GI lack ENS?the most common form of HSCR presents along the distal colon, also known as colonic aganglionosis. The underlying cellular mechanisms that ENPs utilize to migrate into and spatially position along the gut tube, as well as genetic programs they execute to differentiate into enteric neurons have not been well studied in vivo, therefore limiting our knowledge of how the ENS manifests. The overall goal is to expand foundational knowledge of the genes utilized to execute the complex mechanisms necessary for ENS formation, with an eye for informing downstream translational therapeutic studies. In this proposal, we utilize zebrafish embryos due to their genetic conservation with humans, the ease of viewing their external development and for their optical transparency. Building off of single-cell transcriptomic data sets generated from ENP cells collected during their early neurogenesis along the gut tube, Aim 1 will examine a hypothesis that the spatial arrangement of newly uncovered ENP transcriptional subpopulations predict future enteric neuron placement and terminal differentiation along the gut tube. In agreement with and extending observations in mammalian models, we have recently discovered that Retinoic Acid (RA) signaling is critical globally during early steps of zebrafish ENS development; however, how RA signaling autonomously influences ENS ontogenesis in vivo is not well understood in any system to date. Aim 2 will investigate a hypothesis that the RA pathway autonomously controls ENP differentiation states and migration patterns along the gut tube using cutting edge single-cell transcriptomics, optogenetics and in vivo imaging. We will also test a mechanistic model in Aim 2 that candidate transcription factors function intrinsically downstream of RA in ENPs to govern ENS formation, thereby expanding our understanding of the ENS gene regulatory network. Aim 3 will use genetic modulation of the cell cycle, quantitative in vivo imaging and cell tracking test a cellular mechanistic model that ENPs couple proliferation with migration to dictate proper enteric neuron patterning in the gut downstream of the RA pathway. The results of these aims will significantly increase our knowledge of the genetic, molecular and cellular underpinnings of ENP development and early ENS creation and they will provide a new mechanistic framework for studying these developmentally important cells in vivo.
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