Giulia Fulci, PhD, Neurosurgery, 2007 Rappaport Research Scholar

The Rappaport Award has been of immeasurable support in allowing Dr. Fulci’s research and career to move forward. Her research focuses on increasing efficacy of oncolytic virotherapy for brain tumors through transient suppression of the host’s innate antiviral defense responses. Oncolytic virotherapy is performed with viruses that selectively replicate in and kill tumor cells. Thus, these viruses can generate a progeny that spreads through the tumor while sparing the surrounding normal tissue. This is an excellent means to deliver an anti-tumor agent to isolated malignant cells that infiltrate the normal brain and that cause rapid re-occurrence of the cancer after standard treatments. Dr. Fulci is currently establishing a new magnetic resonance imaging (MRI) technique that allows monitoring in brain tumor patients the presence of antiviral immune responses, the intratumoral spread of the virus and the tumor response to the treatment throughout the therapy.

In summary, Dr. Fulci is establishing a state-of-the-art diagnostic tool that can evaluate in a quantitative and non-invasive fashion all three parameters and therefore provide fundamental information about the progress of the treatment. Through the Rappaport Family Fund, Dr. Fulci has received the support needed to obtain preliminary data for a National Institutes of Health R21 grant application that was recently awarded. This grant established her as an independent researcher and allows her to pursue her scientific interests. Moreover, her results were recently accepted for a presentation at an international meeting on gene therapy.

Mohammed R. Milad, PhD, Psychiatry, 2007 Rappaport Research Scholar

Dr. Milad’s research focuses on understanding the neurobiology of learning not to fear (fear extinction) in both the rat and human brains. Recently, the department of Psychiatry has built the behavioral neuroscience laboratory to allow Dr. Milad to continue his research. Particular emphasis of this new laboratory is to investigate the differences between males and females in their ability to inhibit fear and to understand the potential influence of gonadal hormones (i.e. estrogen and progesterone) on the neurobiology of fear extinction. The generous support of the Rappaport Family Fund has been instrumental in helping him to initiate this line of his research. The fund has allowed the purchase of animals and supplies for the laboratory. Moreover, the fund is contributing to the salary of a post-doctoral fellow to assist Dr. Milad in conducting his research. Dr. Milad is in the initial phase of gathering preliminary data that will permit him to apply for funding from the National Institutes of Health.

Thus, the support from the Rappaport Family Fund has allowed 1) the initiation of an important line of research to help understand differences between men and women in learning not to fear, 2) the scientific development of a post-doctoral fellow, and 3) the scientific development of a junior faculty member in the department of psychiatry.

Eric M. Morrow, MD, PhD, Psychiatry, 2007 Rappaport Research Scholar

The Rappaport Award has provided important support for Dr. Morrow's research. Dr. Morrow’s research has focused on neurodevelopmental and genetic mechanisms that are root causes of childhood neuropsychiatric illness such as autism and related disorders of cognitive development. During this year, Dr. Morrow has completed 3 projects which are now under review: 1) The first project involves using high-density SNP microarrays to identify loci in patients with autism from special founder populations. These patients were recruited as a part of the International Homozygosity Mapping Collaborative, an international genetics effort that Dr. Morrow co-directs. In this project, mutations in a gene were discovered in a subtype of autism involving comorbid seizure disorder. 2) In a second study, mutations in autism and mild mental retardation were discovered in a gene name alpha-neurexin-1. 3) In a third manuscript under review, Dr. Morrow conducted a mutational analysis of a gene involved in synapse remodeling in a patient cohort from the MGH Schizophrenia Research Program.

Dr. Morrow has applied the Rappaport Fellowship to salary support to provide protected time to complete studies, prepare manuscripts, and travel for international clinical research and national presentations.

Sydney S. Cash, MD, Neurology, 2007 Rappaport Research Scholar

Dr. Cash’s laboratory focuses on trying to understand normal and abnormal oscillations in the human brain. Specifically, he and his team are interested in understanding the mechanisms which underlie rhythmic activity in sleep, cognition and epilepsy. They use both non-invasive and invasive methods to study these phenomena and hope to use these results to improve diagnostic and therapeutic efforts to cure neurological disease.

With help from the Rappaport Family Fund, one of their most exciting research programs focuses on using specialized microelectrodes (shown here) to record from the human cortex and understand how seizures start, spread and stop. About 50 million people worldwide suffer from epilepsy – as many as 1/3 of these patients have seizures which can not be controlled with medications alone. Using these microelectrodes, Dr. Cash and his colleagues have recorded seizure activity in patients undergoing surgery for poorly controlled epilepsy. These studies offer a unique view of the physiology of seizures at a level of detail which has never been achieved in humans before. Early results are promising and suggest new ways to understand how seizures start and spread. Dr. Cash and his team hope to quickly expand on this new understanding and build new systems for detecting, predicting and controlling seizures.

William T. Curry, Jr, Neurosurgery, 2006 Rappaport Research Scholar

The Rappaport Award provided immeasurable support in allowing Dr. Curry’s research to move forward. His team is combining herpes virus treatment of malignant brain tumors with immunotherapy approaches in an attempt to generate more effective and durable strategies for this intractable disease. G47D is a herpes simplex virus type I that has been engineered in the laboratory selectively to replicate in, and, thereby, kill, dividing cancer cells. Normal brain tissue is essentially unaffected. Furthermore, the virus is further mutated so that it does not inhibit the generation of an immune response, and inflammation in the infected tumor is promoted. In mice, they have combined intratumoral injection of this potent virus with intratumoral injection of immature dendritic cells, which are generated by culturing bone marrow cells with particular cytokines. These dendritic cells can then process components of dying tumor and travel to lymph nodes where an antitumor immune response is generated. Their work has demonstrated that this combination viral and dendritic cell therapy is very effective, and, in fact, can cure most established subcutaneous tumors in mice. The researchers are currently working on this model in the intracranial compartment and are also combining oncolytic HSV-1 treatment of tumors with other immune modifiers.

The Rappaport funds provided for animals and reagents for these studies. With these data, Dr. Curry has achieved additional funding from the American Brain Tumor Association to continue this work. Two abstracts have been accepted for presentation at national scientific meetings.

Jonathan Rosand, Neurology, 2005 Rappaport Research Scholar

Dr. Rosand is Assistant Professor of Neurology at Harvard Medical School and Director of Fellowship Training in Vascular and Critical Care Neurology at MGH. His research in the prevention and treatment of hemorrhagic stroke focuses on identifying the genes that underlie the disease. He was recently recruited to the newly formed MGH Center for Human Genetic Research. The Rappaport Family Fund provided support at this crucial time to hire staff to assist Dr. Rosand in the establishment of an infrastructure for research in genetics. With this structure now in place, Dr. Rosand is able to initiate genetic studies independently and is in a much stronger position to apply for federal funds for his research.

Daphne Holt, Psychiatry, 2004 Rappaport Research Scholar

The crucial support of the Rappaport Family Fund has allowed Dr. Holt to complete her studies in the field of schizophrenia functional neuroimaging. Completing and publishing the results of these studies will allow her to become an established investigator in this field, with state-of-the-art-training in the techniques of functional MRI, cognitive neuroscience, and clinical investigation in psychiatry.

Dr. Holt is currently conducting what she hopes will be the definitive functional magnetic resonance imaging study of the neural basis of emotional perception abnormalities in psychosis. The purpose of this research is to identify early markers of illness to allow the development of methods to prevent the onset or slow the progression of schizophrenia. She has evidence that psychotic symptoms are associated with errors in the evaluation of the emotional significance of objects, social interactions and events in the environment. These errors result from a tendency to misattribute emotional significance to neutral or ambiguous information—an “affective misattribution bias.”

To understand the changes in brain function that give rise to this abnormality, Dr. Holt and her team have developed a novel experimental paradigm specifically designed to elicit this bias. Using this paradigm and the spatiotemporal imaging techniques developed at the MGH Martinos Center in Charlestown, her team is attempting to identify the timing and the functional neuroanatomy of this affective misattribution bias in psychotic patients with schizophrenia. After they have characterized the pattern of brain activity associated with this bias in psychosis, they will then determine whether they can detect the identical pattern in at-risk individuals who later go on to develop schizophrenia.

Dr. Robert Carter, Neurosurgery, 2003 Rappaport Research Scholar

Dr. Carter and his team have developed a new strategy for "starving" human brain tumors by decreasing their ability to grow new blood vessels. This was done by creating blocking proteins, which bind to the major molecule, VEGF, that is used by brain tumors to develop new blood vessel growth. With support from the Rappaport Foundation, three different adeno-associated viral vectors encoding these blocking proteins were produced. The team is now in a testing phase of pre-clinical mouse models. The group hopes to complete pre-clinical testing in 2004, and, if successful, apply to the FDA for approval for testing in human brain tumor patients.

Dr. Diana Rosas, Neurology, 2002 Rappaport Research Scholar

Since joining the Neurology faculty, Dr. Rosas has focused her research activities on brain imaging of patients with cognitive disorders, particularly Huntington’s disease. She was promoted to assistant professor at Harvard Medical School and has been successful in getting independent funding from NIH.

As a Rappaport Scholar, she was able to purchase key equipment needed to perform sophisticated data analyses required to develop and validate surrogate biomarkers for Huntington’s disease. She was also able to provide partial salary support for a laboratory research assistant and other related laboratory and office supplies.

Dr. Lee Goldstein, Psychiatry, 2001 Rappaport Research Scholar

Dr. Goldstein has developed a breakthrough optical imaging device that is able to identify a marker of early Alzheimer's disease. Eventually, such a test might be used to measure the effectiveness of new strategies to treat or prevent Alzheimer's symptoms and to diagnose the disease in its earliest stages, when new treatments are likely to be most effective. Dr. Goldstein is associate director for Basic Research at the Center for Ophthalmic Research of the BWH Department of Surgery, a member of the psychiatry departments at MGH and BWH and the MGH Laboratory for Oxidation Biology, and assistant professor of Psychiatry at Harvard Medical School.

Emad Eskandar, Neurosurgery, 2000 Rappaport Research Scholar

Dr. Eskandar is successfully progressing along an academic track with his own lab in the newly developed Center for Nervous System Repair. His research involves the exploration and use of microelectrode recordings to define the function of the basal ganglia and with translational studies to patients with movement disorders and Parkinson's disease.

As a Rappaport Scholar, Dr. Eskandar purchased equipment and software to construct a computer system that collected high-quality intraoperative physiologic data from patients undergoing surgery to treat Parkinson disease. With this system, Dr. Eskandar initiated an IRB approved protocol to study the activity of neurons in the subthalamic nucleus during visually guided movements. The computers and interface cards are used to run the visual experiment and to store and analyze the physiologic data. Dr. Eskandar's group is currently the only one in the world conducting this kind of research. The preliminary results have been extremely interesting and are the subject of upcoming talks at the Congress of Neurologic Surgeons Meeting and American Association of Neurology meeting. In addition, Dr. Eskandar has submitted one paper and is preparing another at the present time.