1985 — 1993 |
Orr, Harry T. |
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 Biological Studies On the Hla System @ University of Minnesota Twin Cities
This proposal is a continuation of our efforts to characterize, using molecular genetics, the class I gene family of the human major histocompatibility complex (MHC). In addition to maintaining the transplantation barrier between individuals, molecules encoded by the MHC have a central role in regulating the immune response. The class I loci constitute a multigene family whose hallmark is a high level of polymorphism. We will continue to focus our attention on the class I gene family of lymphoblastoid cell line (LCL) 721. LCL 721 was chosen because of the large number of HLA deletion mutants which have been derived from it by Dr. DeMars of the University of Wisconsin. These mutants have been used to map DNA fragments to the known HLA-A and -B alleles of LCL 721 (26). Two of these, HLA-A2 and -A1 will be cloned and sequenced as a beginning in understanding the molecular basis of HLA polymorphism. Our mapping studies have also identified class I-like sequences located telomeric to HLA-A2 (19), as an analogous position relative to the MHC as the murine QA-Tla genes. In order to ascertain the relationship between the human class I-like telomeric sequences and the murine Qa-Tla genes, we will obtain genomic clones of the telomeric segments. These will then be subjected to DNA sequencing and studies directed at determining if these sequences include expressed genes. An important aspect will be to determine the tissue distribution of any class I-like genes found to be expresses. Understanding the relationship to the murine Qa-Tla genes of the human class I-like DNA located telomerically to HLA should help to identify useful markers of human lymphocyte differentiation.
|
1 |
1986 — 1987 |
Orr, Harry T. |
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 Genetics of Spinocerebellar Ataxia @ University of Minnesota Twin Cities
Hereditary ataxias are a group of diseases which include spinocerebellar degenerations and olivopontocerebellar atrophies. The Schut-Swier kindred has an autosomal dominant form of spinocerebellar ataxia (SCA) genetically linked to the HLA complex chromosome 6. DNA markers will be isolated from chromosome 6 which permit the delection of polymorphic restriction endonuclease sites in the Schut-Swier kindred. These markers will be mapped to sub-regions along chromosome 6. A panel of mapped markers will then be used to probe genomic DNA from lymphoblastoid cell lines established from 80 members of the Schut-Swier kindred. These data will be analyzed for restriction fragments linked to the SCA gene. The establishment of a linked marker(s) to SCA will permit: 1) The identification of individuals carrying the SCA gene within the Schut-Swier kindred. This information will enable more precise genetic counseling. Members of this kindred have proven to be very responsive to past counseling by Dr. Schut. 2) Determining if SCA in other kindreds is due to a mutation in the same locus as the Schut-Swier kindred, 3) The use of molecular biological methods to isolate and characterize the SCA gene.
|
1 |
1988 |
Orr, Harry T. |
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 Genetics of the Cerebellum @ University of Minnesota Twin Cities
Hereditary ataxias are a group of diseases which include spinocerebellar degenerations and olivopontocerebellar atrophies. The Schut-Swier kindred has an autosomal dominant form of spinocerebellar ataxia (SCA) genetically linked to the HLA complex chromosome 6. DNA markers will be isolated from chromosome 6 which permit the delection of polymorphic restriction endonuclease sites in the Schut-Swier kindred. These markers will be mapped to sub-regions along chromosome 6. A panel of mapped markers will then be used to probe genomic DNA from lymphoblastoid cell lines established from 80 members of the Schut-Swier kindred. These data will be analyzed for restriction fragments linked to the SCA gene. The establishment of a linked marker(s) to SCA will permit: 1) The identification of individuals carrying the SCA gene within the Schut-Swier kindred. This information will enable more precise genetic counseling. Members of this kindred have proven to be very responsive to past counseling by Dr. Schut. 2) Determining if SCA in other kindreds is due to a mutation in the same locus as the Schut-Swier kindred, 3) The use of molecular biological methods to isolate and characterize the SCA gene.
|
1 |
1990 |
Orr, Harry T. |
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. |
Behavioral Genetics/Biology of Aging @ University of Minnesota Twin Cities |
1 |
1990 |
Orr, Harry T. |
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. |
Research Training -- Behavioral Genetics @ University of Minnesota Twin Cities |
1 |
1992 — 1995 |
Orr, Harry T. |
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 Genetics of the Sca1 Locus On Chromosome 6p @ University of Minnesota Twin Cities
The long term objective of the proposed work is to isolate and characterize the gene for the neurodegenerative genetic disorder spinocerebellar ataxia (SCA). The approach will be to first identify DNA markers that will enable the precise chromosomal localization of the SCA gene by linkage using two very large SCA families and the CEPH panel of reference families. The next step will be to use DNA markers that are close to the SCA gene by DNA cloning. Once the gene is isolated, it will be possible to determine the alteration that results in SCA. This will provide important insights into the development of this cerebellar degenerative disease and may also provide clues into the genetic basis of other neuronal degenerative diseases.
|
1 |
1993 |
Orr, Harry T. |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
International Workshop On Chromosome 6 @ University of Minnesota Twin Cities
Funds are requested to support the First International Workshop to determine the status of the genetic and physical map of chromosome 6. The workshop will be entitled "Present Status and Future Strategies for Mapping Chromosome 6". As this represents the first workshop devoted exclusively to chromosome 6, an important aspect win be to bring together scientists with the appropriate genetic and biological resources and expertise to expedite the completion of the map of chromosome 6. The conference draws strength from The University of Michigan Human Genome Center and Cancer Center and emphasis will be placed on new technologies for generating large numbers of chromosome 6-specific gene sequences. One of the most important aspects of this workshop will be to broaden and facilitate collaborative efforts and to foster more extensive scientific exchange between investigators focusing efforts on mapping of chromosome 6. This workshop will serve as a focal point for determining available resources, developing new technologies, and employing efficient methods for ultimately completing a detailed genetic and physical map of chromosome 6.
|
1 |
1995 — 1999 |
Orr, Harry T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Hereditary Ataxia--Molecular Genetics &Pathophysiology @ University of Minnesota Twin Cities
The inherited spinocerebellar ataxias (SCAs) are a heterogenous group of disorders characterized by variable degrees of degeneration of the cerebellum, spinal tracts, and brain stem. The primary ataxias are currently, for the most part, poorly understood. This multidisciplinary Program Project proposal is designed to address the SCAs using genetic, molecular, and pathophysiological approaches. This proposal brings together a group of investigators from the clinical and basic sciences committed to obtaining new information that will further our understanding of the hereditary ataxias. The Program consists of two support cores, administrative and clinical, and four scientific projects. The long term goals of these projects are: Project 1: To develop and characterize a transgenic mouse model of spinocerebellar ataxia type 1 (SCA1). This will be achieved by using the SCA1 gene recently identified by Dr. Orr and colleagues. Project 2: To examine the molecular aspects of the CAG trinucleotide repeat unstability associated with SCA1. Molecular studies will be performed using patient sperm, cell lines, and transgenic mice developed in Project 1. Project 3: To use a positional cloning strategy to localize and isolate the gene affected in a large ten generation kindred with an autosomal dominant SCA, designated as LSCA. By linkage analysis, LSCA is distinct from SCA1, SCA2, and Macchado-Joseph disease. Project 4: To study the metabolic anatomy and pathophysiology of hereditary ataxias (SCA1 and LSCA) using the quantitative imaging techniques of [18F]fluorodeoxyglucose (FDG) and [150]Water positron emission tomography. (PET) Core A (Clinical): To provide several important clinical supportive functions, including neurological assessments, maintenance of a Ataxia Database, autopsies, and collection of sample material for future genetic studies.
|
1 |
1995 — 1999 |
Orr, Harry T. |
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. |
Hla-G and Maternal/Fetal Immune Interactions @ University of Minnesota Twin Cities
During normal pregnancy, a semiallogeneic fetus is not rejected by the maternal immune system. The unique pattern of class I major histocompatibility complex (MHC) antigen expression seen at the human maternal/fetal interface is thought to be vital for proper fetal immune status. The lack of polymorphic class I and II MHC antigens on trophoblasts the only fetal tissue in direct contact with the mother, is likely to be at least a part of the explanation of fetal evasion of allograft rejection. The observation that the HLA-G-encoded class I MHC molecule is present on certain subpopulations of cytotrophoblasts suggests this nonpolymorphic molecule may have a role in the maternal/fetal immune response and, possibly, have a role in maintaining the immunoprivileged status of the fetus. In this request for continued support, we propose to examine the regulation and immunological role of class I MHC gene expression at the maternal/fetal interface using transgenic mice. Transgenic mice carrying a genomic fragment from the HLA-G locus express the HLA-G gene in their extraembryonic tissue in a pattern similar to the extraembryonic expression of HLA-G during human gestation. This transgenic model system will be used to delineate the cis-acting DNA elements required for proper spatial and temporal (developmental) expression of HLA-G in extraembryonic tissue. In addition, transgenic mice will be used to assess the recognition of HLA-G by T cells and whether HLA-G transgenic mice are tolerant to HLA-G. If tolerance to HLA-G is demonstrated, we will determine the role of the thymus in the induction of this tolerance. We also propose to examine the effect of extraembryonic expression of HLA-G on the maternal decidual T cell population. Finally, the role of HLA-G expressed at the maternal/fetal interface in presenting foreign antigen to the maternal immune system will be assessed.
|
1 |
1996 — 1997 |
Orr, Harry T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Generation of Purkinje Neurons in Transgenic Mice @ University of Minnesota Twin Cities
Project I of this Program Project Grant seeks to study the neurodegeneration associated with SV40 T antigen expression in Purkinje precursor cells and neurons. Using regulatory DNA elements from a Purkinje cell-specific gene, Pcp-2, transgenic mice have been established that express SV40 T antigen in their cerebellar Purkinje cells. Embryonic expression of SV40 in one line, SV5, results in an arrest of cerebellar development. In two other lines, SV4 and SV6, transgene expression initiates in Purkinje neurons after their migration to and maturation in the cerebellar cortex. In these lines, SV40 T antigen induces Purkinje cell degeneration. A series of experiments are proposed to characterize the molecular basis of the induction of Purkinje cell death by SV40 T antigen. In addition, neuropathological studies will be performed on these transgenic lines to further characterize the effects of Purkinje cell death. The goals are to understand the molecular basis of this neurodegeneration and to assess whether these genetic models will provide insights into neurodegenerative diseases in general.
|
1 |
1996 — 1999 |
Orr, Harry T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Murine Model of Hereditary Ataxia Sca1 @ University of Minnesota Twin Cities
Recently, in collaboration with Dr. Huda Zohgbi (Baylor) we showed that spinocerebellar ataxia type 1 (SCA1) is due to an expansion of an unstable CAG repeat within the ataxin-1 gene on human chromosome 6p. The goal of the work proposed in this project is to study the biology of the ataxin-1 gene in the mouse. This will be achieved by: 1) Examining the tissue and developmental pattern of ataxin-1 expression in the mouse using in situ hybridization, and 2) The development and characterization of a mouse model of SCA1. Our laboratory has considerable expertise in the use of transgenic mice to study cerebellar Purkinje cells (a major site of cellular degeneration in individuals affected with SCA1). Thus, we are positioned to determine if transgenic mice expressing an expanded allele of the SCA1 gene are a suitable model of, 1) the human disease, and 2) a genetically unstable CAG repeat. A mouse model of SCA1 will provide valuable information concerning the function of ataxin-1 gene in normal cerebellar physiology, the pathologenesis of SCA1. Transgenic mice, carrying human ataxin-1 genes with various CAG repeat configurations, will also be examined as possible models for unstable (intergenerational) trinucleotide repeats.
|
1 |
1996 — 2010 |
Orr, Harry T. |
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. |
Molecular Genetics of the Sca1 Locus @ University of Minnesota Twin Cities
Spinocerebellar ataxia type 1 (SCA1) is one of a series of autosomal dominant cerebellar ataxia. SCA1 patients develop gait ataxia, dysarthria and nystagmus. As the disease progresses other signs of cerebellar and brainstem dysfunction become apparent with death resulting from loss of bulbar function. Neuropathology in SCA1 includes severe loss of cerebellar Purkinje cells. SCA1 is among a group of neurodegenerative disorders caused by an expansion of a CAG triplet repeat encoding a polyglutamine tract within each respective disease protein. Substantial progress has been made towards understanding the molecular basis of SCA1 pathogenesis. However, several critical questions remain for SCA1 and for polyglutamine disorders in general. These, for the most part, relate to the relative importance of the polyglutamine tract vs. its protein context for driving disease. We propose a model of SCA1 pathogenesis in which disease ensues due to a disruption of nuclear architecture and/or function in specific neurons by mutant ataxin-1 (the SCA1 gene product). In this model, there are predicted to be several points at which residues in ataxin-1 that, along with the polyglutamine tract, would have a critical role in driving the development and progression of disease. The aims of this proposal use a genetic approach to testing several important aspects of this model in transgenic mice: 1) Whether disease progression requires the transport of mutant ataxin-1 to the nucleus, 2) Whether disease progression is dependent on the ability of mutant ataxin-1 once in the nucleus to induce alterations in nuclear structure/function, 3) To examine the role of the nuclear proteins that interact with ataxin-1 in SCA1 pathogenesis, and 4) Examine the importance of the timing of mutant ataxin-1 expression on disease progression. Understanding the importance of these factors for SCA1 pathogenesis should provide insights for polyglutamine diseases in general.
|
1 |
1999 — 2002 |
Orr, Harry T. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Molecular Genetics of Purkinje Cell Function @ University of Minnesota Twin Cities
The overall goal of the experiments proposed in this Project is to study the role of the CREB system in Purkinje cell synaptic plasticity in the cerebellar cortex. The CREB system was selected for analysis in the cerebellum because of the large accumulation of evidence from diverse systems and species demonstrating that this group of transcriptional factors has a critical role in signaling between the synapse and the nucleus. Given the specificity of the Pcp-2/L7 regulatory elements to direct expression to Purkinje cells, the experimental approach to be used offers a distinct advantage in that it will enable us to examine the role of CREB in a select population of neurons within the mammalian brain. Furthermore, these experiments will enable an activator form of CREB to be expressed in Purkinje cells providing the first direct test of CREB activator function in a mammalian neuronal cell type. It should also be noted that all transgenic mice will be generated using an inbred strain, FVB/n. Thus, there will be no variation in genetic background between littermates except for that due to the presence or absence of the transgene. Finally, demonstrating a functional importance for CREB in the cerebellar cortex will provide important molecular support that this region of the brain is involved in motor learning. The specific aims to be pursued are: 1) To examine whether the disruption of CREBs within Purkinje cells of the cerebellar cortex alters their function and morphology. This will be accomplished by the over-expression of ICER in Purkinje cells in transgenic mice using Pcp-2 regulatory elements. 2) To use a regulatable model of ICER expression to directly correlate disruption in CREB with alterations in Purkinje cell function. 3) To further examine the role of CREB in Purkinje cell function, we will establish transgenic mice with induced expression of a CREB activator isoform.
|
1 |
2000 — 2002 |
Orr, Harry T. |
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 Characterization of Sca7 @ University of Minnesota Twin Cities
DESCRIPTION (From the applicant's abstract): Spinocerebellar ataxia type 7 (SCA7) is among a group of neurodegenerative disorders caused by an expansion of a CAG triplet encoding a polyglutamine tract within the disease protein. While substantial progress has been made towards understanding the molecular basis of pathogenesis for some SCAs, it is still uncertain the extent to which residues outside of the polyglutamine tract are important for disease. Using a strategy that has proven very effective for elucidating molecular features of SCA1 pathogenesis, the applicants propose to examine the molecular basis of SCA7 pathogenesis. The aims of this application are: To use transgenic mice to examine Purkinje cell pathology induced by mutant ataxin-7 and to test whether the subcellular localization of mutant ataxin-7 is important for the induction of Purkinje cell disease in vivo. To examine whether the same features found to be important for ataxin-7-induced Purkinje cell disease in aim 1 are critical for the ability of mutant ataxin-7 to induce disease in other neurons. To accomplish this, SCA7 transgenic mice with expression of ataxin-7 in photoreceptors, a neuronal cell type affected in SCA7, will be generated and characterized. Transgenic mice will also be developed to examine the ability of mutant ataxin-7 to induce disease in neurons throughout the brain. To gain insight into ataxin-7 function a series of experiments are proposed to characterize the cellular and subcellular expression of ataxin-7 and to identify proteins that interact with ataxin-7 using the yeast two-hybrid system.
|
1 |
2003 — 2021 |
Orr, Harry T. |
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. |
Cell Signaling and Neurodegeneration @ University of Minnesota
DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an untreatable fatal autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ATXN1. Previous work has shown that the sub cellular deposition and localization of mutant ATXN1 plays a critical role in the pathogenesis of SCA1. For many proteins, the peptide backbone is often altered by post-translational modifications (PTMs) and covalent attachment of chemical groups that change the properties, and hence the function of proteins. ATXN1 is modified by phosphorylation at two sites, S776 and S239. In addition this protein is sumoylated at a minimum of five lysine residues, one of which is in the AXH domain a region of ATXN1 important for several crucial interactions. Thus the goal of the studies proposed in this application is to elucidate the pathways that lead to the phosphorylation and sumoylation of ATXN1 in vivo. We will assess the extent to which the post-translational modification of ATXN1 impact its biology, in particular the ability of mutant ATXN1 to cause the degeneration of cerebella Purkinje cells. PUBLIC HEALTH RELEVANCE: In undertaking these studies we are focused on testing two hypotheses: 1) Post- translation modifications are important for regulating the normal function of ATXN1 and pathogenesis induced by mutant ATXN1, and 2) As such they are targets for development of treatments for SCA1.
|
1 |
2005 — 2006 |
Orr, Harry T. |
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.) |
Modulation of Ataxin-1 Phosphorylation @ University of Minnesota Twin Cities
DESCRIPTION (provided by applicant): Spinocerebeltar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCAl-encoded protein ataxin-l. The subcellular localization and deposition of mutant ataxin-1 is a critical factor in the pathogenesis of SCA1. The mechanism(s) that control these events are not understood, however, phosphorylation is a mean to control protein localization and degradation. We sought to determine if ataxin-1 is phosphorylated, and have shown that serine 776 (S776) of both wild type and mutant ataxin-1 is phosphorylated in vivo and in vitro. Preventing phosphorylation of this residue by replacing it with alanine results in a mutant protein found in the nucleus that is not pathogenic. The goal of the research described below is to develop a cell culture based assay that can be used to screen a compound library for modulators of ataxin-1 serine 776 phosphorylation. Such a screen will identify new molecular tools to aid in elucidating the mechanism of SCA1 pathogenesis. Moreover, identified compounds will provide potential leads toward the development of a therapeutic treatment for SCA1. Lead compounds that have been validated will be used to begin preclinical testing using a mouse model of SCA1.
|
1 |
2011 — 2021 |
Orr, Harry T. |
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. |
Molecular Genetics of Sca1 @ University of Minnesota
DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an inframe CAG trinucleotide repeat. Each repeat tract encodes a stretch of glutamine residues in the affected protein, in the case of SCA1 the protein is ataxin-1 (ATXN1). Symptoms of SCA1 include loss of motor coordination and balance, slurred speech, swallowing difficulty, spasticity, and some cognitive impairment. A characteristic feature of SCA1 pathology is atrophy and eventual loss of Purkinje cells from the cerebellar cortex. Like many neurodegenerative disorders, SCA1 is typically a late onset disease suggesting that physiological changes due to aging contribute to the onset of the disease. There is currently no effective treatment. Thus, identifying signaling pathways and cellular mediators of SCA1 onset and progression remain a major challenge in the search for therapeutics and is the focus of the research outlined in this application for continued support. ) PUBLIC HEALTH RELEVANCE: We hypothesize that distinct cellular pathways underlie the two stages of SCA1 disease. 1) The S776/RBM17-mediated disease initiation early progression (pathogenesis), and 2) polyglutamine, age-related late progression. The long-term goal of this work is to use information obtained about these pathways to identify novel avenues for therapeutic development. )
|
1 |
2011 — 2015 |
Orr, Harry T. |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Genetic Manipulation Core @ University of Minnesota
Purpose of the Core: The Genetic Manipulation Core provides Center investigators with the ability to manipulate gene expression in vitro and in vivo. This Core incorporates a twopronged strategy so that investigators can select the optimal method to meet their needs. The AAV Division provides recombinant viruses for manipulating target expression for instances where acute manipulation is sufficient. For those investigators requiring the ability to manipulate gene expression chronically in vivo, the Core provides bacterial artificial chromosome (BAC) transgene construction. An added advantage of this Core design is that it provides an investigator with the ability to first test a particular manipulation using the less expensive viral vector approach and then move to a BACbased approach as appropriate. For example, the Orr group is actively trying to identify the kinases and phosphatases that regulate the phosphorylation of ataxin-1 at Ser776, since this posttranslational modification is thought to regulate the normal function of the protein as well as SCA1 pathogenesis by mutant ataxin-1. Having the ability to modify the activity of enzymes in vivo Figure 2. Floorplans showing Core facilities for the Center (areas enclosed by red boxes), using recombinant viral vectors provides a very useful screen of candidates from cellular and biochemical studies before moving into transgenic mouse studies using a BAC-based approach
|
1 |
2013 |
Orr, Harry T. |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Aim 2014 Conference @ University of Minnesota
PROJECT SUMMARY/ABSTRACT A wide range of acquired and genetic insults cause ataxia, a disabling and frequently fatal neurological disorder. The 5th Ataxia Investigators' Meeting, AIM 2014: Advancing Toward Therapeutics, will assemble an international roster of investigators to address the multi-disciplinary nature of ataxia, to define better the pathogenic basis of ataxia, and to explore routes to therapy for what is largely an untreatable disease. The conference will focus on the most recent scientific advances and emerging translational approaches toward therapy, with the following five objectives: 1) Enhance the open exchange of information related to ataxia research; 2) Stimulate collaborative research between investigators worldwide; 3) Improve our understanding of human ataxic disorders; 4) Provide junior investigators with an opportunity to present their work, interact with more established scientists in the field, and have an opportunity to interact with patients and support groups so that they can see the clinical impact and importance of their work. AIM 2014 will represent a critical mechanism to facilitate collaboration and discussion on ataxia research and therapeutic approaches, which is of particularly great importance now that the field is entering the phase of meaningful, multi-center clinical trials both in the United States and Europe. The location of the AIM 2014 meeting, dovetailing with the annual meeting of the largest ataxia foundation in the country occurring at the same hotel, will maximize the impact of this meeting for scientists and patients alike. PUBLIC HEALTH RELEVANCE: AIM 2014 will focus on the most recent advances in ataxia research and therapeutic approaches for ataxic disorders. Ataxia, which is broadly defined as the loss of motor control, can affect all aspects of human movement gait, dexterity, speech, swallowing, and eye movements, and afflicts approximately 1 in every 2,000 individuals worldwide. Emerging genetic understanding of ataxias has recently led investigators to envision common pathogenic mechanisms and possible shared therapeutic approaches. These new concepts in disease targets and therapeutic strategy demand increased communication and collaboration among scientists and clinicians so that therapies can be developed, which is a primary goal of AIM 2014. This meeting will also provide a forum for recruiting new investigators to this field of research, which is a critically important element toward achieving rapid translational success.
|
1 |
2015 — 2018 |
Orr, Harry Akkin, Taner [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Uns: Developing Serial Optical Coherence Scanning to Reveal White Matter Changes in Sca1 @ University of Minnesota-Twin Cities
PI: Akkin, Taner Proposal Number: 1510674
The objective of this project is to develop an optical imaging technique to study the anatomical changes associated with spinocerebellar ataxia type 1 (SCA1), which is a fatal inherited neurodegenerative disease. Development of the optical technique will enable a comprehensive three-dimensional (3D) reconstruction of the brain and cerebellum, and support quantitative assessments on white matter content and organization. The obtained information may result in the identification of specific markers of the disease and support development of therapeutics in the future.
Serial optical coherence scanning (SOCS) integrates a tissue slicer and a multi-contrast optical coherence tomography for large scale brain imaging at high resolution. It distinguishes white matter and gray matter, and visualizes nerve fiber tracts that are as small as a few tens of micrometers. The retardance contrast due to axonal birefringence highlights the nerve fibers, while the axis orientation contrast indicates their orientation in the plane. In addition, the Purkinje cells and microstructures in gray matter can be visualized by incorporating a microscope objective. The development of SOCS will include a calibration path for obtaining the absolute axis orientation of nerve fibers in the xy plane, and imaging at multiple illumination angles to extract the inclination angle of the fibers with respect to the z-axis. This would represent the fiber orientation in 3D. It will also allow for calculation of the true birefringence. SOCS will be used on three different SCA1 mice models. The investigators hypothesize that as disease progresses towards death of Purkinje cells in nonlethal (ATXN1-82Q) and lethal (SCA1-154Q/2Q) forms, it will manifest in the local and global characteristics of the white matter, which is the axonal and probably the disease carrying pathway to the brainstem and other brain regions. Neither the Purkinje cell death, nor the premature death of the animal occurs for ATXN1-30QD776 mice, which will serve as the control group. Comparative studies will result in better understanding of the SCA1. The project also aims to integrate the research effort with the educational activities that involve general public and students. An exhibit at the Science Museum of Minnesota will be developed for broad dissemination of knowledge to enhance understanding of biomedical optics and the optical imaging technology that allows for high resolution visualizations of the brain. The content will be incorporated in a biomedical optics course taken by both undergraduate and graduate students.
|
0.915 |