2008 Research Awards

Neuroendocrine Regulation of Glioblastomas

PI: Ian Dickerson, Ph.D.
Co-Investigator: Ed Brown, Ph.D.

Malignant glioblastomas are highly aggressive brain tumors characterized by rapid proliferation, invasiveness, high vascularization, and resistance to apoptosis and thus most chemotherapy and radiotherapy. Patients generally survive less than two years from diagnosis. Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) are two neuropeptides that have potential to inhibit glioma proliferation and angiogenesis. Our hypothesis is that by disrupting the receptor for these peptides or by expressing their antagonists we can inhibit glioma cell survival. We will use a combined biochemical and in vivo imaging approach to directly test the requirement for AM and CGRP in in situ glioma growth and angiogenesis. The specific aims are to:

1. Disrupt the AM and CGRP receptor in glioma cells,
2. Express the antagonist for CGRP in glioma cells, and
3. Express the antagonist for AM in glioma cells.

Modified glioma cells will be implanted into cranial windows of mice, and tumor proliferation and angiogenesis will be monitored by 2-photon microscopy. These studies will directly determine the role of CGRP and AM in autocrine glioma proliferation and paracrine angiogenesis. The studies described in this proposal represent a new collaboration between the Brown lab and the Dickerson lab to bring to bear our combined expertise in neuropeptide biochemistry, cancer biology and in vivo microscopy to identify novel therapeutic targets for glioblastoma treatment. These studies will produce basic knowledge on glioblastoma proliferation and angiogenesis, and provide data for follow-on NIH proposals to study the role of AM and CGRP in glioma tumor growth, and for development of high-throughput screens to identify compounds that disrupt receptor function, which represent a new class of compounds for glioma therapy.

Functional Plasticity of Language

PI: John Langfitt, Ph.D.
Co-Investigator: Elissa Newport, Ph.D., Madalina Tivarus

Under normal circumstances, language abilities in human adults (both speaking and comprehension abilities) are controlled by specific areas in the left hemisphere of the brain; the right hemisphere controls other many other cognitive functions but is not primarily involved in language. However, when the left hemisphere is injured early in life, the brain can adapt by having the right hemisphere assume many of these language functions. The goal of this project is to study patients who experienced early disease or injury to the left hemisphere, to see how this reorganization takes place. Using fMRI and behavioral testing techniques, we will identify those language functions that do and do not shift readily to the right hemisphere, and also determine the specific areas in the right hemisphere that assume language functions when a shift occurs. This information will provide important insights into the those brain areas and language functions that adapt best, and will suggest how such reorganization takes place. Our hope is that such research can lead to the development of therapies that promote the inherent ability of the brain to repair itself.

Deficits in auditory and vestibular function in episodic ataxia type-1: a comparison of auditory and vestibular function in human patients and mouse models

PI: James R. Ison, Ph.D., Dept Brain and Cognitive Sciences (UR)
Co-Investigators:

• Gary Paige, M.D., Ph.D., Dept Neurobiology and Anatomy (UR)
• Rudolf Rübsamen, Ph.D., Institute of Biology-II (U Leipzig)
• Bruce Tempel, Ph.D., Dept Otolaryngology (U Washington)

I currently study neuronal development, particularly the formation of the initial segment in spinal motor neurons, in Dr. Peter Shrager’s laboratory, using cell biology, molecular biology and electrophysiology techniques. I have become interested in research in Dr. Roman Giger’s laboratory, which is focused on axon regeneration after spinal cord injury. This fellowship will provide me an opportunity to gain new knowledge and acquire techniques in a related area. I intend to find an independent research position in an area related to spinal cord injury in the future.

We will study hearing and the sense of balance in human patients who suffer transient loss of motor control (patients diagnosed with Episodic Ataxia Type 1 EA1); and also in genetically-engineered mouse models of EA1. The genetic basis of this motor disorder is one of several types of mutation in a gene (Kcna1) that controls the excitability of nerve cells important for motor control. This gene is also present in neurons that are critical for hearing and for the sense of balance, but nothing is known about hearing and balance in these patients. Through parallel studies of hearing and balance in patients and in one EA1 mouse model as well as in a Kcna1 knockout mouse, and through coordinated electrophysiological analyses in these mice, we will gain a better understanding of the neural pathways that are not functioning properly in these patients. To the extent that the results in mice are similar to those found in patients, then we will be able to use the animal model to develop and test potential types of therapy for EA1 patients. One unusual feature of this research program is that the interdisciplinary work will be carried out in laboratories located in three institutions, the University of Rochester, the University of Washington, and the University of Leipzig, by neuroscientists with different but inter-related specialized research skills, all sharing an interest in the genetic foundation of normal and abnormal sensory and motor function.

Influence of Reward on Response Control in Parkinson's Disease

PI:Martha Johnson-Gdowski, Ph.D.
Co-Investigators:

• Michelle Burack, M.D., Ph.D.
• Mark Mapstone, Ph.D.
• Jon Mink, M.D., Ph.D.
• Jason Schwalb, MD

In 2005, the Johnson Gdowski laboratory received a Schmitt research grant with co-Principal Investigator Jason Schwalb, M.D. to study sensorimotor integration in aging and in Parkinson’s Disease (PD). Working with collaborator, Jonathan W. Mink, M.D., Ph.D., this funding allowed us to develop equipment and to collect data that are being prepared for publication. The project has fostered additional collaborations and new research directions. The new proposal utilizes much of the same equipment and analysis developed under the original research proposal. However, we will incorporate new technology to expand the sophistication of experimental task presentation and control. We also include two new collaborators (Co-PI Michelle Burack, M.D., Ph.D., a board certified neurologist and movement disorders specialist and Mark Mapstone, Ph.D., a neuropsychologist).

An increasing number of reports in the literature suggest that some treatments for PD, while providing improvements in motor function, may negatively impact cognitive function and/or decision-making. Reports of patients that have been treated using dopamine replacement drugs or using deep brain stimulation (DBS) in the subthalamic nucleus (STN) have indicated an increase in the impulsivity of responses in choice/decision making tasks. These functions may be more severely impaired when decisions yield negative outcomes. This means that treated Parkinson’s patients have difficulty correcting behavior based on punishment, but can improve performance if the outcome of their decisions is rewarding. It is this aspect of sensorimotor integration and cognitive decision making that we will pursue in this study.

The purpose of the proposed experiments is to evaluate the influence of reinforcement on sensorimotor integration in patients that have been diagnosed with PD. We will evaluate the influence of positive (reward), neutral, and negative (punishment) feedback upon cued motor responses by quantifying reaction time, movement time, spatial and temporal aspects of arm movement, and the generation of errors. Our subject pool will be comprised of control individuals and patients with subthalamic nucleus deep brain stimulators (STN-DBS). PD patients with STN-DBS will be tested under various treatment conditions (on/off meds and on/off stimulation) to directly evaluate the role of basal ganglia circuitry in reinforcement-based control of motor responses. Ultimately, the goal is to use correlations between reinforcement-based motor responses and patient-specific modeling of DBS stimulus volumes to modify DBS programming to minimize adverse behavioral side effects of STN stimulation.

Can Pain Cause Arthritis?

PI: Stephanos Kyrkanides, Ph.D., D.D.S.
Co-Investigators: Kerry O’Banion, M.D., Ph.D.

During the course of arthritis, sensory nerves transmit pain signals from the joints to the brain. Inflammation then develops at specific locations in the spinal cord, which in turn appears to be important in the maintenance of joint pain. To this end, we hypothesize that this spinal cord inflammation is also important in the maintenance and aggravation of joint arthritis through the release of factors from the nerves, which promote inflammation, into the joint. Our research will focus on one such factor, namely calcitonin gene-related peptide (CGRP) and will evaluate its role in the development of osteoarthritis in a laboratory animal model.

Post-Doctoral Awards

Encoding prior knowledge for probabilistic decision making in neural circuits

PI: Jan Drugowitsch, Ph.D.
Mentors: Alex Pouget, Ph.D., Greg DeAngelis, Ph.D.

Symposium

Multi-Sensory Integration Underlying Communication and Navigation

Liz Romanski and William O’Neill

Speakers:

• UR—Charles Duffy, Greg DeAngelis, William O’Neill, Lizabeth Romanski
• Guests—Jennifer Groh, Jeff Taube, John Foxe, Walter Metzner