1989 — 2020 |
Doe, Chris Q. |
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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Genetic and Molecular Studies of Neurogenesis
DESCRIPTION (provided by applicant): We are investigating how the central nervous system (CNS) is assembled during embryonic development. This is has several potential human health benefits relevant to the NIH mission. First, the treatment of many neurological disorders would benefit from a method for generating specific types of neurons from the patient's own induced pluripotent stem (IPS) cells. Second, many psychiatric disorders arise in part from developmental defects. Generating therapeutic tools to treat these types of disorders will require a detailed understanding of how each neuronal subtype is normally formed. We have been investigating this question in the model organism Drosophila, which has been profoundly important for discovering mechanisms of neurogenesis relevant in mammals. Much is currently known about how neural progenitors acquire their spatial identity (e.g. forebrain vs. hindbrain) but we still know very little about how they sequentially produce different cell types. We previously identified a series of transcription factors that specify temporal identity within the Drosophila nervous system. Here we focus on three related questions in embryonic progenitors (Aims 1-3) and conclude with the first analysis of temporal identity in a newly discovered Drosophila post- embryonic neural progenitor that shares features with the primate outer ventricular zone progenitor (Aim 4). In Aim 1, we will determine whether the Hunchback transcription factor acts transiently in progenitors or continuously in post-mitotic neurons to specify first-born temporal identity. Because the mammalian Hunchback ortholog Ikaros has a similar role in specifying early-born retinal ganglion cell fates, this aim has the potential to hep design therapeutic treatments to replace a cell type essential for human vision. In Aim 2, we follow up on results from the previous funding period showing that neural progenitors lose competence over time to form early-born neuron subtypes in response to a pulse of Hunchback expression. We will determine the mechanism of progressive loss of competence in these progenitors, aided by the identification of a nuclear protein whose expression mimics the competence window, and whose prolonged expression can extend the competence window. In Aim 3, we initiate work on a new Type II neural stem cell that we and others recently discovered. Each brain lobe contains 8 type II neuroblasts that divide asymmetrically to produce a series of intermediate neural progenitors (INPs) that each also divide asymmetrically to make a sequence of 10-12 neurons. We will characterize the relationship between neuroblast or INP birthorder and the production of distinct neural subtypes. We have recently identified transcription factors expressed in sequentially in INPs, and we will determine if they specify temporal identity in these sublineages.
|
1 |
1999 — 2002 |
Doe, Chris Q |
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. |
Molecular Genetic Analysis of Asymmetric Cell Divisions
Asymmetric cell divisions, which produce daughter cells with different fates, are important for generating cell diversity during embryonic development, and may regulate stem cell function in many tissues (e.g. epidermis, intestine, blood, liver, germ cells, and the nervous system). Despite the clinical importance of understanding the regulation of asymmetric cell divisions, remarkably little is known about how and where asymmetric divisions occur in mammals. Our long-term goal is to identify genes controlling asymmetric cell divisions in Drosophila, and to determine if homologous murine genes control asymmetric cell divisions during embryogenesis or in adult stem cell populations. The proposed research may have clinical applications in mammalian stem cell immortalization, gene therapy, and treatment of stem cell neoplasms. We will focus on Drosophila CNS stem cells (neuroblasts), which divide asymmetrically to produce a new neuroblast and a more differentiated daughter cell (GMC). At least 4 proteins are partitioned into the daughter GMC, including the Prospero transcription factor, which is necessary for the transition from neuroblast-specific to GMC-specific gene expression. The specific aims of this proposal are: (1) To identify new genes regulating neuroblast asymmetric cell divisions. We will screen for mis-localization of Prospero protein, and characterize mutants by standard molecular genetic methods. (2) To characterize miranda, a gene encoding a novel coiled-coil protein required for the asymmetric localization of Prospero in neuroblasts. We will sequence protein-positive miranda EMS alleles that affect Miranda localization (3 alleles) or Prospero binding (2 alleles) to map each functional domain; use a yeast two hybrid screen to identify proteins specifically binding the Miranda localization domain; screen for novel Miranda- binding "cargo" proteins; and determine the structure of Miranda functional domains (with Dr. M. Churchill). (3) To further characterize prospero function. We will determine if prospero RNA translational repression in neuroblasts (but not GMCs) is necessary to establish distinct sibling fates; assay the role of phosphorylation in Prospero localization; and assay prospero expression and function in the adult sensory nervous system. (4) To isolate murine homologues of miranda (and genes identified in Specific Aim 1), and to characterize their role in regulating asymmetric divisions during embryogenesis and in adult stem cells. We will do RNA and protein localization studies; our collaborator, Dr. G. Oliver will generate and assay the gene knock-out mice.
|
1 |
2001 — 2019 |
Doe, Chris Q |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Developmental Biology Training Grant
DESCRIPTION (provided by applicant): This application is to renew support for a developmental biology graduate training program. Funds are requested for nine predoctoral positions, within a developmental biology research program that includes approximately 66 graduate students and 47 postdoctoral trainees. Over the past year the program has added three new faculty working on developmental biology of the mouse ~ a new research area for this program - as well as adding three faculty trainers in the area of evolution/development. These changes add new strengths and breadth to our core developmental biology training program. The proposed training program emphasizes individualized graduate research training within a group of interactive faculty that provides each student with diverse training input, and a number of students have co-advisors allowing them to integrate research training from two laboratories. Each predoctoral student is advised by a faculty committee that guides the student through a highly individualized training program;the committee meets at least once every year, in addition to many informal meetings (e.g., journal clubs and research seminars), resulting in excellent monitoring of the student's progress and the creation of a supportive environment. Twenty training faculty directly participate in the program. Faculty are all members in the Institute of Molecular Biology (ten), the Institute of Neuroscience (seven), or the Department of Biology (three). The University of Oregon's research Institutes provide an interactive investigative environment;they bring together laboratories with common interests, run graduate programs, provide space and funding support, and have annual retreats. Institutes also support shared research facilities - such as the Genomics and Proteomics Center, Transgenic Mouse Facility, Monoclonal Antibody Facility, and Bio-Optic Center - all staffed with expert personnel who are available to the students for training and assistance in experimental design. The Institute of Molecular Biology and Institute of Neuroscience together provide an interdisciplinary approach to developmental biology that includes computational biology, structural biology, cell biology, neuroscience, and evolutionary biology. This breadth of training combines well with the highly focused project-oriented research training the students receive in their host laboratories, producing creative scientists who will be able to develop their own first-rate research programs, thereby strengthening the national resource in developmental biology. PUBLIC HEALTH RELEVANCE: Training in Developmental Biology is essential to understand the mechanisms that go awry in many diseases, including a number of devastating birth defects such as lissencephaly. Many adult onset diseases, such as numerous cancers, appear to be due to developmental programs that are inappropriately expressed in the adult. The best way to understand, and thus design treatments, for these diseases is to train basic and clinical scientists in developmental biology.
|
1 |
2004 — 2021 |
Doe, Chris Q |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Developmental Biology Training Program
DESCRIPTION (provided by applicant): This application is to renew funding for a training program leading to the Ph.D. degree and providing for professional careers in research and teaching in developmental biology. Support is requested for eight predoctoral positions, within a program that includes approximately 78 graduate students and 45 postdoctoral trainees. The program emphasizes individualized research training under the mentorship of the training faculty. A number of students have co-advisors and research programs that integrate the research expertise in two laboratories, illustrating the collaborative nature of the program. Each predoctoral student is advised by a faculty committee that guides the student through a highly individualized training program; the committee meets at least once every year, in addition to many informal meetings (e.g., when the student presents journal clubs or research seminars), resulting in excellent monitoring of the student's progress and the creation of a supportive and nurturing environment. Sixteen training faculty directly participate in the program. All hold appointments in the Departments of Biology or Chemistry as well as being members in the Institute of Molecular Biology (nine faculty), Institute of Neuroscience (six faculty), or both Institutes (one faculty). The University of Oregon's research institutes provide a close association for laboratories with common interests, facilitating interactive research, and graduate training. The Institutes support shared specialized research facilities - such as the Genomics and Proteomics Center, Monoclonal Antibody Center, and Bio-Optic Center - all staffed with expert personnel who are available to the students for technological training and assistance in experimental design. Involvement of the Institutes in this program provides an interdisciplinary approach to developmental biology that ranges from structural biology/proteomics to computational biology to cell biology and to neuroscience. This breadth of training combines well with the highly focused project-oriented training the students receive in their host laboratories, leading to the training of creative scientists who will be able to develop their own first-rate research programs, thereby strengthening the national resource in developmental biology.
|
1 |