PH SENSITIVE COMPLEX HYDROGELS FOR PROTEIN DRUG RELEASE
M Anthony
University Of Texas Austincity: Austin country: United States (us)
Grant 5R01EB000246-18 from National Institute Of Biomedical Imaging And Bioengineering
Keywords: absorption; Acids; Adhesives; Advanced Development; Agreement; Applications Grants; Attention; Bacterial Adhesins; Belief; Biological Availability; Blood Circulation; Calcitonin; Carbohydrates; Carrier Proteins; Cell model; commercialization; Complex; Compliance behavior; controlled release; cytotoxicity; Development; diabetic rat; Drug Delivery Systems; Drug Design; Drug Formulations; Drug Transport; Engineering; Environment; enzyme activity; Epithelial; Epithelial Cells; ethylene glycol; Ethylene Glycols; Exhibits; gastrointestinal; Gastrointestinal tract structure; Gastrointestinal Transit; Gel; Glucose; Goals; Grant; Hydrogels; improved; In Vitro; in vivo; Insulin; Intestinal Mucosa; Intestines; Isoelectric Point; Lead; Legal patent; Liquid substance; Membrane; methacrylic acid; Methodology; Molecular; monolayer; Nature; novel; novel strategies; novel therapeutics; Oral; Oral Administration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Polymers; Property; Proteins; public health relevance; Pyrrolidis; Research; Research Design; residence; Resistance; Rodent Model; Route; Series; Simulate; Small Intestines; Solubility; Somatotropin; Stomach; Structure; success; System; Testing; therapeutic protein; Time; Transferrin; Universities; Vertebral column; Work
Relevance: STATEMENT OF PUBLIC HEALTH RELEVANCE There is a general scientific belief that oral delivery of protein drugs such as insulin, calcitonin, and growth hormone is impossible due to the protective nature of the GI tract and extensive proteolytic activity of enzymes in the GI tract. We have developed a novel, complexation hydrogel system that has been engineered to protect the protein drugs in the GI tract and enhance transport of the drugs into the bloodstream. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy
Project start date: 1989-12-01
Project end date: 2015-02-28
Budget start date: 1-MAR-2012
Budget end date: 28-FEB-2013
5R01EB000246-18 (2012): $396041
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to M Anthony
PH SENSITIVE COMPLEX HYDROGELS FOR PROTEIN DRUG RELEASE
M Anthony, Fletcher S. Pratt Chair In Eng
University Of Texas Austincity: Austin country: United States (us)
Grant 2R01EB000246-17A2 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: This is a resubmission of a competing renewal proposal of grant RO1 EB000246-17 for the continuation of our studies on the fundamental understanding of transmucosal delivery of drugs, peptides and proteins using a series of novel biopolymeric complexation carriers with unique properties and in advanced controlled release systems. It has generally been believed that peptides and proteins such as insulin cannot be administered via the oral route because of their degradation by the proteolytic enzymes in the gastrointestinal tract and their extremely slow rate of transport across the mucosal membrane. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy. Our group has developed a new class of polymeric complexation hydrogels comprised of poly (ethylene glycol) (PEG) chains grafted on poly (methacrylic acid) (PMAA) backbone chain. The new systems, henceforth designated as P (MAA-g-EG), have shown extreme promise as oral delivery vehicles for insulin, calcitonin, and growth hormone. Prior studies have established that these systems are promising candidates for oral delivery of insulin. Yet, our more recent work and attention is now focused on continued strategies for enhancing the bioavailability of oral delivered proteins, in addition to insulin. The methodologies we intend to pursue in this competing renewal proposal include (i) developing further strategies for protection of the protein in the GI lumen; (ii) enhancing transport of the proteins across the GI lumen; and (iii) increasing the residence times in the upper small intestine through enhanced bioadhesion. While some strategies have been previously investigated with moderate success using insulin, in this work, we will pursue novel strategies that may provide significant advances over our prior studies with insulin. Additionally, we intend to further develop these complexation hydrogels for oral delivery of other therapeutic proteins such as calcitonin and growth hormone. There is a general scientific belief that oral delivery of protein drugs such as insulin, calcitonin, and growth hormone is impossible due to the protective nature of the GI tract and extensive proteolytic activity of enzymes in the GI tract. We have developed a novel, complexation hydrogel system that has been engineered to protect the protein drugs in the GI tract and enhance transport of the drugs into the bloodstream. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy
Keywords: 1, 2-Ethanediol; 2-Hydroxyethanol; 2-methylacrylic acid; absorption; Absorption; Acids; adhesin; Adhesins, Bacterial; Adhesives; Administration, Oral; Advanced Development; Agreement; Alimentary Canal; alimentary tract; Applications Grants; Attention; backbone; Bacterial Adhesins; Belief; Bioavailability; bioavailability of drug; Biologic Availability; Biological Availability; Blood Circulation; Bloodstream; bowel; Calcitonin; Calcitonin(1-32); Calcitrin; Carbohydrates; Carrier Proteins; Cell model; Cellular model; Circulation; commercialization; Complex; Compliance behavior; compliance cooperation; controlled release; cytotoxicity; D-Glucose; Development; Dextrose; diabetic rat; diabetic rat model; digestive canal; Digestive Tract; Dihydroxyethanes; Drug Administration, Oral; Drug Delivery; Drug Delivery Systems; Drug Design; Drug Formulations; Drug Targeting; Drug Targetings; Drug Transport; drug/agent; Drugs; Engineering; Engineerings; Environment; enzyme activity; Epithelial; Epithelial Cells; Esteroproteases; Ethanediols; ethylene glycol; Ethylene Glycols; Exhibits; fluid; Formulation; Formulations, Drug; gastric; gastrointestinal; Gastrointestinal Tract; Gastrointestinal tract structure; Gastrointestinal Tract, Small Intestine; Gastrointestinal Transit; Gel; gene product; GHN; GI Tract; Glucose; Goals; Grant; Grant Proposals; Grants, Applications; Granulocyte/Pollen-Binding Protein; Growth Hormone; Growth Hormone 1; heavy metal lead; heavy metal Pb; hGHN; Humulin R; Hydrogels; improved; In Vitro; in vivo; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin, Regular; Intestinal; Intestinal Mucosa; Intestines; Intestines, Small; intraoral drug delivery; Isoelectric Point; Lead; Legal patent; liquid; Liquid substance; Lytotoxicity; Medication; Membrane; membrane structure; methacrylic acid; Method LOINC Axis 6; Methodology; Molecular; Monoethylene Glycol; monolayer; Nature; new approaches; new therapeutics; next generation therapeutics; novel; novel approaches; novel strategies; novel strategy; novel therapeutics; Novolin R; Oral; Oral Administration; Patents; patient adherence; Patient Compliance; Patient Cooperation; Pb element; Peptidases; Peptide Hydrolases; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physiologic Availability; Pituitary Growth Hormone; Polymers; Process of absorption; Property; Property, LOINC Axis 2; Proteases; Proteinases; Proteins; Proteolytic Enzymes; public health relevance; Pyrrolidis; Pyrrolidones; Rat model of diabetes; Research; Research Design; residence; Resistance; resistant; Rodent Model; Route; Series; Siderophilin; Simulate; small bowel; Small Intestines; Solubility; somatotropic hormone; Somatotropin; Spinal Column; Spine; STH; Stomach; Structure; study design; Study Type; success; System; System, LOINC Axis 4; Testing; therapeutic protein; therapy compliance; therapy cooperation; Thyrocalcitonin; Time; Transferrin; Transport Proteins; Transporter Protein; Treatment Compliance; Universities; Vertebral column; Work
Relevance: STATEMENT OF PUBLIC HEALTH RELEVANCE There is a general scientific belief that oral delivery of protein drugs such as insulin, calcitonin, and growth hormone is impossible due to the protective nature of the GI tract and extensive proteolytic activity of enzymes in the GI tract. We have developed a novel, complexation hydrogel system that has been engineered to protect the protein drugs in the GI tract and enhance transport of the drugs into the bloodstream. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy
Project start date: 1989-12-01
Project end date: 2015-02-28
Budget start date: 5-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-10-067
2R01EB000246-17A2 (2011): $452074
FUNCTIONAL MICROCIRCUITRY UNDERLYING SOUND PROCESSING IN THE PRIMARY AUDITORY COR
M Anthony, Associate Professor
Cold Spring Harbor Laboratorycity: Cold Spring Harbor country: United States (us)
Grant 5R01DC005415-09 from National Institute On Deafness And Other Communication Disorders
Abstract: The long-term goal of our investigations is to understand the functional role of certain neuronal subtypes in the processing of sound in the cortex. Understanding this circuitry is likely to have an impact on the diagnosis and treatment of clinically important cortical neuropathologies, including autism, schizophrenia, tinnitus and epilepsy. Our central hypothesis is that a certain subtype of inhibitory neuron plays an important role in determining how other cortical neurons respond to sound. To achieve our goals, we propose to monitor and perturb the activity of these neurons. In aim 1, we will study this circuit in vitro, substituting electrical for auditory stimulation. In aims 2 and 3 we will study this circuit in vivo, presenting simple sounds and monitoring the responses they elicit in single neurons, and looking at their role in an auditory behavior. If successful, our studies will provide the link between molecular, circuit and functional aspects of sound processing in the auditory system, and will facilitate the development of treatments for psychiatric and neurological diseases. This proposal will test the function of a particular class of cortical neurons implicated in the etiology of clinically important neuropathologies, including autism, schizophrenia, tinnitus and epilepsy. If successful, our studies will lead to improved strategies for diagnosing and treating these and related disorders
Keywords: Accounting; Acoustic Nerve; Acoustic Stimulation; Acute; Area; area V1; Auditory; Auditory area; Auditory system; Autistic Disorder; awake; base; Behavior; Brain; Characteristics; Complex; Diagnosis; Disease; Epilepsy; Equilibrium; Etiology; extrastriate visual cortex; Goals; Grant; improved; In Vitro; in vivo; Individual; inhibitory neuron; Interneurons; Investigation; Lead; Link; Mediating; Mental disorders; Methods; millisecond; Molecular; Molecular Profiling; Monitor; nervous system disorder; Nervous system structure; neural circuit; neuromechanism; neuronal circuitry; Neurons; neuropathology; Parvalbumins; Pattern; Physiological; Physiology; Play; Population; Positioning Attribute; Preparation; Process; Property; Rattus; receptive field; relating to nervous system; Relative (related person); Reporting; response; Rodent; Role; Schizophrenia; Sensory; sensory cortex; sensory neuroscience; sensory stimulus; Shapes; Slice; sound; Synapses; Techniques; Testing; therapy development; Tinnitus; tool; Visual Cortex; Work
Relevance: This proposal will test the function of a particular class of cortical neurons implicated in the etiology of clinically important neuropathologies, including autism, schizophrenia, tinnitus and epilepsy. If successful, our studies will lead to improved strategies for diagnosing and treating these and related disorders
Project start date: 2002-04-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01DC005415-09 (2011): $354339
HIGH-THROUGHPUT DNA SEQUENCING METHOD FOR PROBING THE CONNECTIVITY OF NEURAL CIRC
M Anthony, Associate Professor
Cold Spring Harbor Laboratorycity: Cold Spring Harbor country: United States (us)
Grant 5R01NS073129-02 from Office Of The Director, National Institutes Of Health
Abstract: The brain is an extremely complex network, consisting of billions of neurons connected by trillions of synapses. The details of these connections-which neurons form synaptic connections with which other neurons-are crucial in determining brain function. Malformation of these connections during prenatal and early postnatal development can lead to mental retardation, autism or schizophrenia; loss of specific connections later in life is associated with neurodegenerative diseases such as Alzheimer´s. An efficient method for determining the brain´s wiring diagram would transform neuroscience research. We propose to develop a method for exploiting high-throughput DNA sequencing to probe the connectivity of neural circuits at single-neuron resolution. Many neuropsychiatric and neurodegenerative diseases, including autism, schizophrenia, mental retardation and Alzheimer´s disease, result in the loss of specific connections in the brain. We propose to develop a method for identifying these connections in animal models of disease. Our method will have a profound impact on understanding the causes of these diseases
Keywords: Alzheimer`s Disease; Animal Disease Models; Autistic Disorder; Brain; Complex; Development; Disease; DNA Sequence; Lead; Life; malformation; Mental Retardation; Methods; neural circuit; Neurodegenerative Disorders; Neurons; neuropsychiatry; Neurosciences Research; postnatal; prenatal; public health relevance; relating to nervous system; Resolution; Schizophrenia; Synapses
Relevance: Many neuropsychiatric and neurodegenerative diseases, including autism, schizophrenia, mental retardation and Alzheimer´s disease, result in the loss of specific connections in the brain. We propose to develop a method for identifying these connections in animal models of disease. Our method will have a profound impact on understanding the causes of these diseases
Project start date: 2010-09-27
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-RM-09-022
5R01NS073129-02 (2011): $430650
M Anthony, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 2R01EY015790-06A2 from National Eye Institute
Abstract: Sensitivity to motion and binocular cues are both of vital adaptive significance. While single unit studies have provided detailed information on the spatio-temporal dynamics of direction-selectivity and binocularity in individual cortical areas and human fMRI studies have mapped slow hemodynamic responses in multiple human visual areas, neither approach provides an analysis of the functional dynamics of these networks. We have developed EEG-based source-imaging and signal analysis tools that we will use to develop predictive dynamical models of motion processing and binocular interaction throughout cortex at a spatial resolution that is on the order of 2 cm or less. In Aim 1 we will use EEG-source imaging and perceptual measurements to compare the functional form of spatio-temporal interactions underlying long- versus short-range apparent motion and to map their sites of generation. Direction-specific adaptation will be used to confirm which response components are due to motion mechanisms. We will also vary the observer´s task in order to determine the extent of top-down (feedback) influences on apparent motion processing. A bistable apparent motion stimulus will be used to compare responses during episodes when apparent motion is perceived to when it is not. In Aim 2 we will apply recent technical developments in EEG source-imaging to the study of motion responses in the extra-striate cortex of typically developing humans infants between two and six months of age. These data will be used to test models of motion processing and to identify periods of rapid development. In Aim 3 we will study the relationship between intact motion processing and functional binocular interaction in patients with strabismus/amblyopia. Across the three Aims, four independent criteria (cortical locus, developmental dissociation, dependence on attention and pattern of non-linear interaction) will be used to provide converging evidence regarding the existence of multiple motion processing sub-systems as predicted by psychophysicists. The methods of dynamic functional imaging that will be developed in this proposal will provide a powerful new approach for understanding normal and abnormal visual processing throughout development. Because these methods are applicable in human, they provide an important translational bridge between direct neural measurements that can only be done in experimental animals and functional studies of the intact human brain, including studies of patients undergoing treatment
Keywords: Adult; Affect; Age-Months; Amblyopia; Animals; Area; area striata; Attention; base; Behavioral; Binocular Vision; Brain; Cells; Cues; Data; Dendrites; Dependence; Development; Dissociation; Electroencephalography; Evolution; experience; extrastriate visual cortex; Eye; Eye Movements; Failure (biologic function); Feedback; Functional disorder; Functional Imaging; Functional Magnetic Resonance Imaging; Generations; hemodynamics; Human; Human Development; Image; Individual; Infant; insight; Judgment; Macaca; Maps; Measurement; Measures; Methods; Modeling; monocular; Motion; motion sensitivity; novel; novel strategies; optic flow; Patients; Pattern; Perception; Process; Psychophysiology; relating to nervous system; Resolution; response; Role; Sensory; Series; Signal Transduction; Site; Source; Staging; Stimulus; Strabismus; Structure; Synapses; System; Testing; tool; vision development; Visual Cortex; Visual evoked cortical potential; Visual Motion; visual process; visual processing; Visual system structure
Relevance: The methods of dynamic functional imaging that will be developed in this proposal will provide a powerful new approach for understanding normal and abnormal visual processing throughout development. Because these methods are applicable in human, they provide an important translational bridge between direct neural measurements that can only be done in experimental animals and functional studies of the intact human brain, including studies of patients undergoing treatment
Project start date: 2004-09-06
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-10-067
2R01EY015790-06A2 (2011): $468187