Charles Horn, PhD - US grants

DESCRIPTION (provided by applicant): Some medications produce nausea and vomiting that may lead to loss of appetite and reduced food intake, which can negatively affect recovery from disease. Nausea and vomiting are frequently observed with use of cytotoxic chemotherapy agents. Little is known about the neural pathways and mechanism for detecting toxins. Gastrointestinal (GI) sensory nerve fibers play an important role in the initiation of vomiting, and may also be involved in the stimulation of nausea. The present proposal will focus on identifying the pathways and neurochemistry of GI vagal and spinal afferent fibers and brain nuclei that are activated by toxins. To address this issue experiments will be conducted to examine the effects of cisplatin (a chemotherapy agent) and lithium chloride (LiCI) (treatments that produce nausea in humans) on visceral afferent nerve activity and brain and spinal cord Fos expression. Studies will determine: (1) the properties (neurotransmitter receptors, stretch-sensitivity, site of innervation in the stomach and intestine) of vagal and spinal afferent fibers responsive to cisplatin and LiCI using a novel application of single-unit neurophysiology, (2) the brainstem and spinal cord sites that are activated by cisplatin and LiCI treatment using Fos expression, (3) the peripheral neural pathways involved in brain Fos expression produced by cisplatin and LiCI using lesions of the vagus and GI spinal nerves, and (4) the neurotransmitter receptors that play a role in the brain Fos response produced by cisplatin and LiCI treatment. An understanding of the physiology of toxin detection may contribute to nausea treatment in a large number of clinical situations, including cancer chemotherapy, diabetic gastroparesis, anorexia nervosa, ischemic gastropathy, chronic intestinal obstruction, abdominal malignancy, and functional dyspepsia. Effective treatment of nausea may substantially improve the quality of life for patients with chronic disease.

Twenty-six mathematics, biology and chemistry majors are preparing to teach in South Carolina high needs schools. Noyce scholars are being selected from a combination of juniors and seniors completing a four year certification program, fifth year students who have completed the requirements a bachelors degree in a STEM major and are seeking teaching certification, and STEM graduates looking for a career change. Undergraduates receive annual scholarships of $10,000 for a maximum of two years. The fifth year students and career changers are eligible for one year scholarships of $25,000. Thirty-four freshmen and sophomore STEM majors with an interest in teaching as a career are participating in six week paid summer internships to investigate teaching via field experiences and enroll in two education courses.

Master Teachers mentor the summer interns and Noyce scholars throughout the scholarship period and the following service obligation. The newly certified teachers are teaching in high needs schools in Laurens 56 School District, Newberry County School District and Lexington 1 School District.

DESCRIPTION (provided by applicant): Nausea and vomiting are common highly aversive experiences for patients with gastrointestinal disease and result in reductions of appetite, qualit of life, and adherence to medications with these side effects. Progress in understanding the biology and treatment of nausea and vomiting has been slow partly because there is currently no focused scientific meeting to discuss and collaborate on these research topics. The current R13 application is a request to support a comprehensive scientific conference on the mechanisms of nausea and vomiting, International Conference on Nausea and Vomiting 2013, to be held at University of Pittsburgh (October 3-4, 2013). This conference will substantially contribute to the goal of the National Commission on Digestive Diseases to understand the noxious visceral signaling causing nausea and vomiting related to gastric neuro-electrical and/or motor dysfunction and the bi-directional brain-gut interactions. There are four objectives of the conference: 1) Provide a forum for cross-disciplinary exchange of ideas to advance research on the biological mechanisms for nausea and vomiting, 2) Foster interactions for young investigators to present research findings and connect with laboratories and more senior investigators working in the field of nausea and vomiting research, 3) Offer a forum where scientists and clinicians who treat patients with nausea and vomiting can exchange information, and 4) Produce an overview and discussion of the major unresolved questions in nausea and vomiting biology and provide the latest methodology. The conference will include five primary sessions: 1) Personalized Medicine and Genetics; 2) Gastroparesis and Cyclic Vomiting Syndrome; 3) Vestibular and Gastrointestinal Integration; 4) Assessment and Control of Nausea; and 5) Cellular Biology and Future Directions. Speakers will present cutting edge research on nausea and vomiting related to gastroparesis, pregnancy, cyclic vomiting syndrome, motion sickness, and drug responses (chemotherapy, opioid analgesics) using genetic, electrophysiological, neuroimaging, and electronic patient reporting approaches. A scientific poster session featuring young investigators will also be provided. The proceedings of the conference will be published in a peer-reviewed journal: Experimental Brain Research. Conference attendees will primarily include scientists (neuroscience, nutrition, and pharmacology), physicians (gastroenterology, oncology, and anesthesiology), and other heathcare providers (nurses, nutritionists). Emphasis will be placed on attendance by early stage investigator faculty and trainees to facilitate the next generation of researchers.

? DESCRIPTION (provided by applicant): Nausea and vomiting are common highly aversive experiences for patients with gastrointestinal disease and result in reductions of appetite, quality of life, and adherence to medications with these side effects. Progress in understanding the biology and treatment of nausea and vomiting has been slow partly because there is currently no focused scientific meeting to discuss and collaborate on these research topics. The current R13 application is a request to support a comprehensive scientific conference on the mechanisms of nausea and vomiting, Biology and Control of Nausea and Vomiting 2015, to be held at University of Pittsburgh (October 23-24, 2015). This conference will substantially contribute to the goal of the National Commission on Digestive Diseases to understand the noxious visceral signaling causing nausea and vomiting related to gastric neuro- electrical and/or motor dysfunction and the bi-directional brain-gut interactions. There are five objectives of the conference: 1) Provide a forum for cross-disciplinary exchange of ideas to advance research on the biological mechanisms for nausea and vomiting; 2) Foster interactions for early-stage investigators to present research findings and connect with laboratories and more senior investigators working in the field of nausea and vomiting research; 3) Offer a forum where clinicians who treat patients with nausea and vomiting can exchange information; 4) Produce an overview and discussion of the major unresolved questions in nausea and vomiting biology and provide the latest methodology; and 5) Broadly disseminate the findings and consensus of the meeting in peer-review manuscripts. The conference will include six primary sessions: 1) Prodromal responses and signs of nausea; 2) Acute-to-chronic nausea and vomiting; 3) Cyclic vomiting syndrome research symposium; 4) Early-stage investigator symposium; 5) Clinical panel discussion; and 6) Cyclic vomiting syndrome adult guidelines session. Speakers will present cutting edge research on nausea and vomiting related to gastroparesis, pregnancy, cyclic vomiting syndrome, motion sickness, and drug responses (e.g., chemotherapy) using genetic, electrophysiological, neuroimaging, and patient reporting approaches. A scientific poster session will also be provided. The proceedings of the conference will be published in a peer- reviewed journal: Autonomic Neuroscience: Basic and Clinical. Conference attendees will include scientists (neuroscience, nutrition, and pharmacology), physicians (gastroenterology, oncology, and anesthesiology), and other heathcare providers (nurses, nutritionists). Emphasis will be placed on attendance by early-stage investigator faculty and trainees to facilitate the next generation of researchers.

? DESCRIPTION (provided by applicant): Nausea and vomiting occur with numerous medical treatments and diseases, including cancer chemotherapy and diabetic gastroparesis, which can lead to reduced appetite and nutritional imbalance. Activation of a gastric vagal neural circuit i believed to play a primary role in emetic signaling; however, gastric vagal emetic signaling essentially remains a black box. The following fundamental mechanistic questions are unanswered: (1) how are emetic signals coded in the vagus by activation of specific fiber subtypes, temporal patterns, or gastric receptive fields? (2) Do different emetic stimuli produce the same vagal emetic message? (3) What are the mechanisms responsible for the history-dependence of the gastric emetic system? The goal of this project is to develop joint electrophysiology and infrared (IR) technology that will permit detailed functional neural circuit mapping for the control of the gastric emetic pathway as a potential therapy for nausea and emesis. Our team has the unique expertise to achieve this goal. Dr. Horn has developed a system to interrogate and analyze the activity of individual vagal units while recording the emetic reflex in the musk shrew (emetic reflexes are absent in rats and mice). Drs. Jenkins and Chiel have initiated work using an IR technology that can stimulate or inhibit sub-populations of axons with high spatial precision. Dr. Lewis has expertise in selectively activating/inhibiting vagal su-populations and in monitoring the molecular biological mechanisms associated with vagal activity. We will complete two AIMS: (1) Develop electrophysiology/IR mapping technology and apply it to characterize the topography and fiber types of gastric afferents within the vagus. To determine how fibers carrying gastric afferent signals are organized topographically within the vagus, we will develop a novel electrophysiology/IR mapping technology. We will develop a multi-optical fiber device that allows illumination of different regions circumferentially, and combine this with an electrophysiological technique that examines individual units in vagal fascicles. (2) Extend the electrophysiology/IR technology to determine and control temporal patterns of vagal activity in response to classical versus clinically relevant emetogenic stimuli. We will examine the patterning of activity in the vagus, and role of IR laser inhibition, in response to stomach-related emetic stimuli, mechanical distension, chemical irritation (using copper sulfate), and the cancer chemotherapy agent cisplatin. Our approach is innovative because we are combining cutting edge electrophysiology and IR technology to develop spatial and temporal maps of the gastric vagal organ system. This project is significant because it will elucidate precise vagal emetic mechanisms that must be modulated to control emesis; therefore, producing the critical knowledge base urgently needed to facilitate the development of new strategies to treat patients with intractable nausea and vomiting. More generally, the technology could have great utility for understanding other aspects of vagal and peripheral nerve function.

Developing more, highly qualified science and mathematics teachers is a national priority. Through funding from the National Science Foundation's Robert Noyce Teacher Scholarship Program, this Phase II Noyce project will continue much of the work initiated in Newberry College's Phase I Noyce award. This Recruit and Engage--Mathematics AND Science Teachers (RE-MAST) Phase II project will produce nine to sixteen additional STEM teachers over the course of the next five years, add leadership and mentor training for all parties in the project, and also conduct a longitudinal study of factors that contribute to Noyce Scholar recipients' pre- and in-service effectiveness and their persistence and leadership in the teaching profession. In this Phase II project, Newberry College will partner with the Retain and Empower Teachers through Action, Innovation, and Networking (RETAIN) Center of Excellence, a state-supported research hub focused on teacher retention, which is currently housed at Newberry College. The partner school districts of Fairfield, Newberry, Lexington, and Richland Counties in South Carolina will provide diverse settings for Noyce Scholars to explore and experience teaching, while at the same time benefitting from the number of nascent STEM teachers with solid backgrounds in science and/or mathematics, pedagogical skills and dispositions of determination for the potential of each student in their classrooms to learn consequential mathematics and science.

Specific activities of the RE-MAST Phase II project include 1) recruiting nine to sixteen additional STEM majors into teaching; 2) delivering educational supports for Noyce Scholars; 3) providing professional development opportunities for Mentors, Noyce Teaching Fellows (former Noyce Scholars), and grant personnel; and 4) pursuing a rigorous research agenda related to teacher retention, or persistence of mathematics and science teachers in the teaching profession. This research study will examine factors at both the program level and the Noyce Scholar level. The project is explicit in its intent to benefit others through the sharing of research derivatives, including protocols, instruments, and professional development materials appropriate for use by practicing school professionals and teacher educators, as well as through scholarly publication of results and findings.

Cytotoxic chemotherapy-induced side effects, including nausea and vomiting, impose a severe physical and emotional burden on cancer patients, which can limit the use of dose-dense curative cancer therapy. Although the exact mechanisms for these adverse effects remain obscure, current theories suggest that vagal sensory signals from the gastrointestinal (GI) tract play a critical role. Until now, it has been impossible to test the function of defined vagal afferent population signaling in these responses to chemotherapy because peripheral neurons could not be selectively, and reversibly, silenced or activated; the optogenetic approach potentially removes this barrier. Here, we propose to use a small animal model for emesis testing (musk shrew) as a platform to assess modulation of GI vagal signaling. Unlike rodents, the musk shrew (a mouse-sized mammal) has a vomiting reflex and is an efficient alternative to ferrets, cats, and dogs for the study of chemotherapy-induced emesis. Our central hypothesis states that vagal afferent neurons can be optogenetically controlled to produce emesis or inhibit chemotherapy-induced emesis. We plan to test this hypothesis by pursuing two specific aims: (1) test the specificity of transport of viral vectors containing light-sensitive opsins, halorhodopsin (for inhibition) and channelrhodopsin-2 (for excitation) in GI vagal afferent populations; and, (2) determine the effects of optical modulation of vagal signaling on emesis. Adeno- associated viruses (AAVs) will be injected into specific stomach regions to infect vagal sub- populations. AAVs will also contain fluorescent reporters to permit the histological examination of sub- sets of nodose ganglia neurons. Specific wavelengths of light applied to AAV loaded vagal fibers will be used to stimulate and inhibit emesis (produced by chemotherapy) in our established in vivo electrophysiology preparation. These experiments will confirm the use of optogenetic methods to modulate vagal sensory transmission. The results of this project with be valuable in the control and testing of emetic mechanisms; similarly, optogenetic methods may be applied to assessing the role of vagal signaling in other diseases affecting cancer patients, including obesity, diabetes, and inflammation.

Gastroparesis has a prevalence of nearly 80,000 people in the USA and is associated with significant morbidity, including chronic nausea and vomiting. Current strategies to control nausea and vomiting in this patient group are largely unsuccessful. Closed-loop neuromodulation technology could potentially provide a precision therapy for these patients because nausea signaling is associated with bioelectric disruption of gastric motility and electrical stimulation of the vagus nerve can increase motility. The goal of the proposed research is to apply closed-loop technology using neuroelectric recording and stimulation devices to improve gastric motility and inhibit emetic signaling. We will initially conduct preclinical testing in ferrets to customize the technology to record gastric myoelectric signals and electrically stimulate the abdominal vagus. The ferret will be used because it is the ?gold- standard? model for emesis testing by industry and is one of the few commonly used models that possesses an emetic reflex, which is lacking in laboratory rats and mice. After proof-of-concept testing in the ferret, we will perform a good laboratory practice (GLP) study in the minipig, a model species for safety testing prior to clinical trials. We will complete the following three Aims: (1) Establish flexible electrode attachment, recording, and stimulation parameters in the ferret. Studies will include testing abdominal vagus nerve stimulation and electrogastrography recording using ultra- precision laser-patterned, and nano-fiber reinforced micro-cuff and conformal planar electrode arrays; (2) Test the efficacy of closed-loop control of emesis in the ferret. Animals will be implanted with vagus and gastric electrodes for awake testing. Emetic-related gastric responses will be produced by gastric emetic stimuli to trigger gastric dysrhythmia and electrical stimulation of the vagus; and (3) Conduct GLP safety testing of electrode implants and abdominal vagus electrical stimulation in the minipig. Animals will be implanted with vagus and gastric electrodes followed by a long-term safety test, with daily stimulation of the vagus. Completion of our Aims will produce the essential efficacy and safety data to enable an Investigational Device Exemption (IDE) submission to the FDA for a subsequent clinical pilot study. This project is significant because it targets an unmet therapeutic need of patients with refractory gastroparesis who experience highly aversive chronic nausea and vomiting.!

Obesity affects almost 40% percent of US adults and is associated with high levels of comorbidities, including cancer, cardiovascular disease, and diabetes. Although effective treatments with minimal side effects are lacking, vagus nerve stimulation (VNS) can reduce body weight and suppress feeding behavior. There is little insight, however, into its mechanism and it is unclear whether VNS effects on feeding and body weight result from non-specific side effects, such as nausea. The current application directly addresses these issues by assessing gastrointestinal (GI) myoelectric changes as a potential mechanism for effects of VNS on feeding behavior, while comparing these responses to emetic activation. We plan to accomplish this by using a ferret model, which is a gold-standard for studying emesis, vagus nerve, and GI physiology. We will test the hypothesis that electrical stimulation of the vagus nerve can reduce food intake without triggering indicators of nausea, such as disrupted GI myoelectric responses, retching, and vomiting. We will complete three Aims. Aim 1: Define the individualized GI myoelectric patterns during feeding behavior using machine learning classification. Animals will be implanted with planar electrodes attached to the GI serosal surface from proximal gastric fundus to distal duodenum. We will use machine learning to classify GI myoelectric patterns of meal consumption compared to emetic-related states, including those elicited by intragastric emetine and high amplitude and frequency VNS known to trigger emesis. Aim 2: Test the efficacy of abdominal VNS on reducing meal size without triggering disruptions of GI myoelectric responses, retching, and emesis. Animals will be assessed for effects of abdominal VNS using a variety of stimulus parameters on feeding behavior and multi-site GI myoelectric recordings. Aim 3: Determine the efficacy of cervical VNS in controlling meal size without producing off-target effects (disruptions of GI myoelectric responses, retching, emesis, changes in heart rate, or blood pressure). We will test the impact of cervical VNS parameters on feeding behavior, GI myoelectric responses, retching, emesis, hear rate variability, and blood pressure. Our approach is innovative because we will use machine learning classification to detect individualized GI myoelectric response patterns in an awake free-moving animal for comparing therapeutic and off-target effects of VNS on feeding, GI activity, emesis, and cardiovascular function. This planned research is significant because VNS therapy can potentially provide a frontline treatment option for patients with high levels of obesity refractory to behavioral or pharmacological therapy, which unlike other surgical interventions for weight loss, such as gastric bypass, is potentially tunable and reversible by changing stimulation parameters, switching the device off, or complete removal.