Gregg E. Homanics - US grants
Affiliations: | University of Pittsburgh, Pittsburgh, PA, United States |
Area:
Transgenic miceWebsite:
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Gregg E. Homanics is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1992 — 1993 | Homanics, Gregg E | 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. |
Making Hepatic Lipase&Lipoprotein Lipase Deficient Mice @ University of North Carolina Chapel Hill disease /disorder model; lipoprotein lipase; lipase; genetic manipulation; laboratory mouse; genetically modified animals; enzyme deficiency; dietary lipid; genetic disorder; biotechnology; blood lipid; lipid metabolism; southern blotting; polymerase chain reaction; genetic recombination; transfection; |
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1995 — 1997 | Homanics, Gregg E | 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. |
Ethanol Mechanisms in Gabaa-R Gene Targeted Mice @ University of Pittsburgh At Pittsburgh Our long-term goal is to define the molecular target(s) of ethanol that explain the neurophysiological basis of intoxication. Several lines of evidence suggest that modulation of the gamma-aminobutryic acid (GABA) neurotransmitter receptor is tat least partially responsible for mediating the acute intoxicating effects of ethanol. To further understand the fuunctional significance of this receptor as it pertains to the mechanism of ethanol intexocation, we propose to use gene targeting in mouse embryonic stem cells to create two novel mouse lines, each containing a defined mutation in the gene encoding the gamma2 subtype of the GABA type A receptor (GABA/A-R). The mouse lines created will be used to test the hypothesis that the gamma2 subtype of the GABA/A-R is critically important to ethanol's intoxicating effects on animals. Both behavioral (loss-of- righting reflex) and subcellular-level (permeability and electrophysiologic) assays will be performed on mutant and wild type mice. The strategic advantage inherent in this proposal is that differences in response to ethanol will be directly linked to single, unambiguous molecular lesions in the gamma2 subtype gene of the GABA/A-R. In this revised application, we describe substantial Preliminary Data (that has been made) at cloning the genomic locus that encodes the gamma2 subtype of the GANA/A-R, at creating targeting constructs, at targeting other loci in embryonic stem cells, at using embryonic stem cells to create chimeric mice, at demonstrating the effects of ethanol on our 36/Cl-influx assay, and trichloroethanol on our electrophysiological assays, and at demonstrating the effects of ethanol on mice in our loss-of-righting reflex assay. |
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1999 — 2019 | Homanics, Gregg E | 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. |
Ethanol Mechanisms in Gabaar Gene Targeted Mice @ University of Pittsburgh At Pittsburgh DESCRIPTION (provided by applicant): This project applies genetic dissection of putative molecular targets of ethanol to explain the neurophysiologic basis of ethanol action. We hypothesize that specific subunits of brain type gamma aminobutryic acid receptors (GABAA-RS) mediate specific behavioral responses to ethanol, as demonstrated for benzodiazepines and intravenous anesthetics. Our work during the previous funding period has (a) provided novel insight into ethanol action, (b) revealed shortcomings of traditional global gene knockout technology, and (c) has demonstrated the promise that conditional knockout and knockin technologies can deliver. The gene knockin and the conditional knockout approaches provide tools to test the GABA hypothesis of alcohol action that are not limited by the problems that plague the global knockout approach. We now propose to analyze genetically engineered mice that harbor ethanol-insensitive, but otherwise normal GABAA-R subunits. GABAA-R mutant mice will be analyzed with a battery of tests that span the molecular, cellular, and behavioral levels. Such a multi-level approach allows a determination of the relevance of a specific drug target (receptor) as a mediator of a specific phenotype (e.g., motor ataxia). These studies could define molecular targets of ethanol action that are responsible for specific clinically relevant behavioral responses. Ultimately that knowledge could lead to novel therapeutic approaches for combating alcohol abuse and alcoholism. |
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2000 — 2001 | Homanics, Gregg E | 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. |
Anesthetic Mechanisms in Gabaa R Gene Targeted Mice @ University of Pittsburgh At Pittsburgh DESCRIPTION (Adapted from applicant's abstract): This proposal is focused on determination of the molecular mechanisms of general anesthetics using transgenic techniques. The investigators will focus on the type A-aminobutryic acid receptor. Mouse lines that ubiquitously lack either the beta3, 26, or delta subunits of the GABAA-R have been produced and studies are underway in these cells/animals. In addition, the researchers proposed to create four further novel mouse lines that harbor tissue-specific knockouts of the GABAA-R2 or beta3 subunits. This conditional knockout approach has major advantages in that untoward developmental effects of the genetic alteration are avoided and the technique permits analysis of the putative neuroanatomic site of action of the anesthetic agents. Finally, the investigators will examine the anesthetic response of three additional genetically altered mouse lines: a) ubiquitous knockout of the alpha1, subunit of the GABAA-R; b) a transgene that expresses an Ala291 Trp point mutation in the alpha1 subunit; c) a knockin mutation of the Ala291 Trp mutation that replaces the endogenous alpha1 gene. |
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2002 — 2006 | Homanics, Gregg E | 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. |
Gabaa-R Alpha4 Subunit in Ethanol-Related Behaviors @ University of Pittsburgh At Pittsburgh DESCRIPTION (provided by applicant): The gamma-aminobutyric acid type A receptor (GABAA-R) has been extensively implicated as a key component of the mechanism of action of ethanol. However, the contribution of individual subunits of the GABAA-R to ethanol-related behaviors has not been adequately addressed. The alpha4 subunit of the GABAA-R has specifically been implicated in modulating behavioral hyperexcitibility in a variety of experimental conditions including ethanol dependence and withdrawal. The use of sophisticated transgenic and gene targeting technology now allows hypotheses to be tested in an unambiguous manner, using precise molecular tools within the context of the whole animal. By testing a variety of mouse models with altered regional and temporal patterns of expression of alpha4 on a battery of molecular, cellular, and behavioral assays, we have the opportunity to elucidate the contribution of the alpha4 subunit to clinically relevant ethanol-related behaviors. We believe these studies provide an integrated approach toward our goal of understanding how ethanol exerts its effects in the central nervous system. To accomplish our goal, the following specific aims are proposed: A1. Create and characterize a transgenic mouse line that overexpresses a tetracycline regulated GABAA-R alpha4 subunit. A2. Create and characterize genetically engineered mice that harbor a ubiquitous knockout of the alpha4 subunit of the GABAA-R. A3. Create and characterize novel transgenic mouse lines that direct inducible, neuron-specific gene recombination. A4. Create and characterize an inducible, neuron-specific GABAAR alpha4 knockout mouse line. A5. Analyze these genetically manipulated animals with a battery of tests to assess basic physiology, behavior, and phenotypic alterations in ethanol-induced behaviors. |
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2004 — 2008 | Homanics, Gregg E | 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. |
Genetic Dissection of Inhaled Anesthetic Targets @ University of California San Francisco This project applies genetic dissection of putative molecular targets of inhaled anesthetics to explain the neurophysiologic basis of their actions. It hypothesizes that type A hippocampal gamma-aminobutryic acid receptors (GABAA-R) mediate part of the amnestic effects of inhaled anesthetics. The project studies hippocampal GABAA-Rs because the hippocampus is central to learning and memory and because inhaled anesthetics enhance the response of GABAA-Rs as do anesthetics (e.g., etomidate) known to cause amnesia by such enhancement. Additionally, a novel genetic approach for creating conditional gene knockin mice will be pioneered. Knockin mice with alterations in specific GABAA-R subunit genes will be created, characterized, and tested. These novel mice will be analyzed in this and other projects within the Program Project with tests spanning molecular, cellular, and behavioral levels. Such a multi-level approach allows a determination of the relevance of a specific drug target (receptor) as a mediator of a specific phenotype (e.g., amnesia). Lastly, collaboration with other project leaders will allow creation of additional genetically engineered mouse lines, including mice with mutant glycine or NMDA receptors, or sodium channels. As with the GABAA-mutant mice, these mice will respond normally to their putative transmitters but will resist the effects of inhaled anesthetics. |
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2008 — 2012 | Homanics, Gregg E | U01Activity 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. |
G Protein Modulation of Glycine Receptor Function and Ethanol Action @ University of Pittsburgh At Pittsburgh [unreadable] DESCRIPTION (provided by applicant): Glycine receptors (GlyRs) play a critical role in neuronal excitability in the mammalian brain stem and spinal cord. Their activation reduces the excitability of neurons associated with sensory information, motor control and respiration, functions that are significantly altered during ethanol (EtOH) intoxication. Studies from our and other laboratories demonstrated that the glycine-activated Cl current can be potentiated by low, clinically relevant EtOH concentrations in native neurons and heterologous expression systems. Studies by Aguayo and others have revealed a novel mechanism of EtOH action on GlyRs that involves modulation by G protein activation. We (Aguayo) recently demonstrated that GlyRs are modulated by G protein ?? subunits via basic residue domains within the TM3-4 intracellular loop of a1-containing GlyRs. Importantly, our preliminary results showed that mutants resistant to G??? dimer modulation were insensitive to potentiation by EtOH. Noteworthy, other receptor properties (apparent agonist and antagonist affinities and single channel conductance) were normal and receptor modulation by general anesthetics was not altered, indicating significant selectivity for EtOH. Altogether, these data demonstrate that basic amino acids in the large intracellular loop regulate the sensitivity of GlyRs to physiologically relevant concentrations of EtOH. However, the prime question that has not yet been answered is: What is the importance of G??? modulation of GlyR function in terms of expression of the clinically relevant effects of EtOH exposure on whole animal behavior? To fill this gap in our knowledge, we propose to extend the pioneering studies of Aguayo to the whole animal level. Our working hypothesis is that EtOH affects GlyR function by free G??? through specific regions in the intracellular loop, and that G??? modulation of GlyRs is critical for the behavioral effects of EtOH. Our primary objectives are to generate gene knockin mice that harbor mutant a1 GlyRs that are insensitive to modulation by G???, and test these mice for cellular and behavioral responses to EtOH. [unreadable] [unreadable] [unreadable] |
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2011 — 2016 | Homanics, Gregg E | U01Activity 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. |
Genetically Engineered Rodent Care @ University of Pittsburgh At Pittsburgh DESCRIPTION (provided by applicant): Genetically engineered rodents are essential for understanding gene function in the context of the whole animal. This is especially important for alcohol research as we ultimately seek to understand the role of individual candidate genes on endpoints that can only be studied at the organism level, e.g., alcohol drinking and alcohol-induced behavioral responses. To service the needs of the INIA-West for genetically engineered animals, this core will provide the following services to consortium investigators. Aim 1 services will provide consultation to investigators regarding model development and construct design. Aim 2 services all relate to gene targeted mouse production including production of targeting vectors, gene targeting in embryonic stem cells, production of chimerical mice, and breeding to establish mutant mouse lines. Transgenic mouse services are the focus of Aim 3. This aim includes transgene production, embryo microinjection, and identification of founder animals. Lastly, Aim 4 involves the application of recently developed zinc-finger nuclease technology to produce knockout rats. Zinc-finger nucleases will be purchased from a commercial vendor and this core will inject them into rat embryos and identify the gene targeted rats that result. PUBLIC HEALTH RELEVANCE: The adverse effects of alcohol are a tremendous burden on our medical system and on our society. The use of genetically engineered rodents allows hypotheses regarding ethanol action to be tested at the organismal level. |
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2017 — 2021 | Homanics, Gregg E | U01Activity 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. |
Role of Noncoding Rna in Alcohol Action @ University of Pittsburgh At Pittsburgh Project Summary Ethanol-induced changes in the brain transcriptome underlie the development and persistence of alcohol use disorder (AUD). INIA-N investigators and others have discovered that ethanol induces specific and dramatic alterations in a highly restricted group of noncoding RNAs (ncRNAs) that includes long ncRNAs (lncRNAs). We posit that these ethanol responsive lncRNAs coordinate AUD brain transcriptomes. Specific Aim 1 will test the hypothesis that individual lncRNAs are key regulators of ethanol drinking. To test this hypothesis, genetically engineered mice with altered expression of lncRNAs will be created and analyzed. Those mutant lines with altered drinking behavior will be scrutinized for mechanistic insight by multiple INIA-N investigators. A barrier to the study of ncRNA function in brain is the dearth of efficient methods of noninvasively delivering ncRNAs and/or ncRNA antagonists to large portions of the brain. Here we posit that intransally administered exosomes (endogenously produced, liposome like nanoparticles) can be harnessed to deliver ncRNA anatagonists or mimics throughout the brain. This approach can also be used to deliver drugs preferentially to brain. Such an approach would target drugs selectively to the desired site of action (brain) while avoiding peripheral toxicities that limit therapeutic efficacy. Because this approach has the dual benefits of target specificity and noninvasiveness, it has tremendous translational potential. Specific Aim 2 will test the hypothesis that exosomes can be harnessed as effective ncRNA/drug delivery vehicles to modulate ethanol drinking. Genetically engineered rodents permit investigation of the involvement of putative ethanol targets in the context of whole animal behavioral responses. Because hypotheses concerning putative ethanol targets must ultimately explain ethanol-induced behavioral phenotypes, whole-animal experiments represent the most rigorous test of relevance. To this end, Specific Aim 3 will create designer mice for both INIA-N and INIA-Stress investigators. Genetically engineered animals will be produced using state of the art CRISPR/Cas9 gene editing technology. This collaborative Specific Aim is the continuation of the INIA-West Genetically Engineered Rodents Core that was funded during the previous project period. |
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