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2008 Young Investigator Award Recipients

POSTDOCTORAL AWARDEES

Sutapa Banerjee, Ph.D., Washington University School of Medicine
Regulation and role of mTOR in neurofibromin growth control
Neurofibromatosis 1 (NF1) is a common cancer predisposition syndrome in which affected individuals are prone to the development of both benign and malignant tumors. In this regard, 15-20% of children with NF1 will develop a brain tumor involving the nerve that carries visual information from the eye to the brain (optic glioma). Studies from the awardees laboratory and others have shown that the NF1 protein, neurofibromin, controls the activity of the mammalian target of rapamycin (mTOR) molecule. It was recently shown that inhibition of mTOR activity in Nf1 mice with optic glioma results in tumor shrinkage. The overall objective of this proposal is to understand how neurofibromin controls mTOR pathway-mediated cell growth in vitro and in vivo. Specifically, Dr. Banerjee plans to determine precisely how mTOR activity is controlled by neurofibromin and how neurofibromin-mediated mTOR pathway activation controls the cancer-related properties of brain cells. These studies are aimed at defining the mechanism underlying neurofibromin growth control relevant to the design of more specific treatments for NF1-associated tumors.

Erika Bell, Ph.D., The Regents of the University of California
Investigation of neurofibromin regulatory mechanisms
NF 1 is a genetic disorder characterized by benign and malignant tumors of the peripheral nervous system (neurofibromas), spotting of the skin (café-au-lait spots), learning disabilities, skeletal abnormalities, and cardiovascular defects. This disease is caused by mutations in NF1, a tumor suppressor gene that codes for the neurofibromin protein. Neurofibromin suppresses cell growth by downregulating Ras signal transduction. Specifically, neurofibromin acts a GTPase activating protein (GAP) to stimulate the hydrolysis of Ras-GTP to Ras-GDP. The GAP activity of neurofibromin is well established, but how this activity is regulated in response to changes in the cellular environment is not well understood. To gain insight into the regulation of neurofibromin Ras-GAP activity, Dr. Bell proposes to study the interaction between neurofibromin and syndecan-4. Syndecan-4 protein binds neurofibromin GAP domain, and therefore may regulate its localization and activity. Syndecan-4 may also contribute to the development of neurofibromas, as it is required for signal transduction in response to a growth factor, TGF-?. Recent studies have shown that mast cells in the neurofibroma microenvironment secrete elevated levels of TGF-b which causes nearby fibroblasts to migrate, proliferate, and synthesize excess collagen. Since collagen accounts for 50% of the neurofibroma weight, inhibition of the fibroblast response to TGF-b could prove a useful treatment for NF1. Dr. Bell proposes to elucidate the role of syndecan-4 in the fibroblast response to mast cell secreted TGF-b.

Johanna Buchstaller, Ph.D., University of Michigan
Tumor initiating cells in MPNSTs
About 10% of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNSTs), soft tissue sarcomas, which are very aggressive and often withstand chemo- and radiotherapy. The awardee’s research group recently showed that plexiform neurofibromas and MPNSTs appear to arise from mature cells found in the nerve bundles of peripheral nerves. The goal for this project is to identify which cells within the tumor drive tumor growth. Previous studies have shown that brain tumor growth is driven by a small minority of cells, whereas the majority of cells within the tumor remain quiescent. This has led to idea that fighting this small subset of cells during cancer therapy might be sufficient to eliminate the cancer. The applicant wants to know if this also applies to MPNSTs and she is going to investigate this issue on mouse models of the disease and human tissue samples obtained by collaborating with the University of Michigan hospital. Preliminary results suggest that a high proportion of cells isolated from MPNSTs are responsible for tumor growth, suggesting that in these cancers all cells are equally able to grow and that tumor therapy will need to target and eliminate all cells. These results now need to be confirmed in a larger number of samples. Additionally, Dr. Buchstaller would like to find out why the tumor cells have the capacity to grow indefinitely. High mobility group a2 (Hmga2) is a molecule that is found in MPNST cells, but not in normal nerve tissue. The applicant will investigate the role of Hmga2 by monitoring tumor development and growth in mice deficient for Hmga2. If fewer and smaller tumors arise in these mice, this suggests that Hmga2 plays a role MPNST growth and that cell signaling pathways involving this molecule might be suitable targets for tumor therapy.
 

Annabel Parret, Ph.D, EMBL, Heidelberg, Germany
Structure determination of neurofibromin by cryo-electron microscopy
NF1 is caused by alterations of a gene encoding a huge protein called neurofibromin that fulfills vital cellular functions and if not functional contributes to the symptoms of NF1, including learning disabilities and cancer related features. Previous work using structural investigation has already contributed and understanding how neurofibromin regulates intracellular signal transduction in order to avoid permanent activation of the cell division machinery and also the discovery of a novel two-component module in the protein whose presence was not detected by other research methods. The 3-dimensional organization of domains within neurofibromin is not known nor the shape of the unknown portions of the protein. One reason for this lack of knowledge is the fact that the full neurofibromin could not be routinely produced for biochemical or structural studies for a long time. The host laboratory has recently succeeded to solve this problem by using modern protein production tools along with the power of modern gene synthesis in vitro. In this study, Dr. Parret will use electron microscopy (EM) to obtain the first 3-dimensional structure of neurofibromin. While EM normally does not give high resolution information it will clearly reveal the shape of the molecule and most likely the locations and relative orientations of the previously structurally characterized portions. This may give insights into aspects of regulation of the protein and/or its binding partners. The study will also lay groundwork for subsequent work employing X-ray crystallography on the side of sample preparation but also by providing an initial model to solve the initial problems of X-ray structure determination.

Aaron Schindeler, Ph.D., The Children's Hospital at Westmead
Mouse models of bone abnormalities in NF1
Congenital pseudarthrosis of the tibia (CPT) is a leading cause of leg amputation in children. Children who develop this condition have bony lesions in the tibia that make it prone to fracture. Once a fracture occurs the tibia fails to unite, leading to a pseudarthrosis or "false joint". Even with modern orthopaedic techniques, sound union is achieved in less than 50% of CPT patients. Permanent disability and/or amputation are common outcomes. At present, patients with CPT undergo demanding recurrent surgery, which is also a major demand on clinical resources. CPT is associated with a loss of the second copy of the Nf1 gene. NF1 is an autosomal dominant disease - the condition arises due to defects in one of two copies of the Nf1 gene. However, a recent clinical study has shown that pseudarthrotic tissues from NF1 patients have undergone a localized loss their second Nf1 gene. Dr. Schindeler will employ several strategies to investigate and model the loss of the second copy of an Nf1 gene in mice. He will make use of conditional knockout technology to delete both copies of the Nf1 gene in mouse tissues. Dr. Schindeler aims to better understand the role of NF1 in bone and in CPT:

With the improved understanding gained from this collaborative research project it is hoped to translate some of the recent breakthroughs in NF1 bone biology to improved outcomes for this neglected patient group.

Weidong Li, Ph.D., University of California, Los Angeles
Ritalin and the treatment of the neurological and cognitive deficits associated with neurofibromatosis type I
Approximately half of children with NF1 show learning disabilities and attention problems. The laboratory has been able to show that mice with a mutation akin to those found in NF1 patients also show learning and attention problems. NF1 mice, as NF1 patients have a molecule called Ras, which is overly active. The lab had previously found that correcting this problem led to a reversal of the learning deficits and attention problems of the mice. Methylphenidate, known commercially as Ritalin, is a central nervous system (CNS) stimulant and a medication prescribed for individuals (usually children) who have attention-deficit hyperactivity disorder (ADHD), which consists of a persistent pattern of abnormally high levels of activity, impulsivity, and/or inattention. Studies showed a high incidence of ADHD in NF1 and supported an association between ADHD and learning and social problems in children with NF1. One clinic report suggested that these NF1 children with ADHD might benefit from the use of Ritalin but the mechanism is unclear. The CNS stimulant role of Ritalin makes it big concern for the parents of NF1 children about the potential of drug abuse. To let the NF1 children get the possible benefits from this drug we need more scientific studies to investigate the effectiveness and mechanism of Ritalin in NF1.Their former studies demonstrated that the cognitive deficits including attention problems are caused by the disruption of neurofibromin function which leads to enhanced Ras-MAPK activities and normalize Ras-MAPK activities could rescue the deficits in NF1 mice. For the proposed study, Dr. Li would test the RAS-MAPK activities and behaviors in NF1 mice by treating with Ritalin. Amazingly, the preliminary studies showed the lower dose but not higher dose of Ritalin might decreases the abnormal higher MAPK activity in NF1 mice, which may account for the effectiveness of Ritalin in NF1. The studies will illustrate why Ritalin may help the cognitive deficits in NF1 and whether the dose is critics for the effectiveness of Ritalin in NF1.

Huarui Zheng, Ph.D., University of Michigan
Therapeutic intervention of preclinical symptoms in a NF1 mouse model
The hallmark feature of NF1 is the development of multiple neurofibromas, which represents major morbidity of NF1 patients. Plexiform neurofibroma is the only type of neurofibroma that has the potential to be transformed to malignant peripheral nerve sheath tumor (MPNST). Currently, there is no effective drug treatment for plexiform neurofibroma. The major therapy strategy is surgical resection. However, plexiform neurofibromas often reside in deep sites of body and diffusely infiltrate through nerves, making it very difficult to resect completely and likely to recur. Therefore, it is urgent and critical for NF1 community to develop new therapeutic strategies based on most recent findings on molecular and cellular mechanisms of plexiform neurofibroma formation. Recently, the lab employed transgenic approaches to generate a mouse model recapitulating human plexiform neurofibromas. By detailed examination of early stage peripheral nerves during neurofibroma development, the group identified cellular mechanism for plexiform neurofibroma formation. Specifically, they found the earliest events of neurofibroma initiation are progressive dissociation of a subset of nonmyelinating Schwann cells (nmSCs) from axons and proliferation, accompanied by axonal degeneration and inflammatory response evidenced by mast cell infiltration. It was also observed elevated mTOR (mammalian target of rapamycin) activity at the stage of neurofibroma development, which suggests a molecular target for preventing neurofibroma initiation. In this proposal, Dr. Zheng will use mTOR inhibitor and mast cell inhibitor to treat the mutant mice from post natal stage to prevent nmSCs dissociation and proliferation, eventually inhibit neurofibroma formation.

PRE-DOCTORAL AWARDEES

Timmy Mani, University of Cincinnati
The role of PIP2 binding and lipid raft association in merlin function
NF2 patients develop a variety of tumors in the brain, the most common being tumors associated with the nerves that are responsible for hearing and sense of balance, leading to difficulties in hearing, ringing in the ears and difficulty maintaining balance. In addition, NF2 patients can also develop several other tumors and the average survival from diagnosis for NF2 patients is 15 years. NF2 patients carry defects in a gene called Nf2, which in normal individuals, produces a protein called merlin. Since the loss of merlin results in tumor formation, the presence of merlin in normal cells is assumed to suppress abnormal cell growth and tumor formation. Experiments from several labs support this hypothesis. However, how merlin prevents abnormal cell growth is not fully understood. The group has shown that merlin is found in specialized regions within the cell membrane, called "lipid rafts", which contain many molecules involved in controlling cell growth and other cell functions. They have also shown that merlin binds to a particular molecule within the cell membrane called PIP2, and that this binding seems to be necessary for its localization to lipid rafts. The overall goals for this study are to determine if PIP2 binding to merlin is essential for the ability of merlin to prevent abnormal cell growth and to determine if PIP2 binding regulates other known modifications of the merlin protein that affect its activity. PIP2 binding represents an important potential mechanism of regulation of merlin function. Understanding the modification of merlin function by PIP2 binding will help facilitate the design of drugs for treating NF2 in future.

Linnea Vose, New York Medical College
Pharmacological effects on cognition in a fly model of NF1
NF1 symptoms include disfiguring benign tumors, an increased risk for malignant tumors, and a high incidence of learning disabilities. Many drugs currently approved for use in humans have the potential to affect proteins in the cellular pathways involved in learning. Mice and flies have genes very similar to the human gene responsible for NF1, and mutations can cause learning defects similar to human patients, making these animals excellent models for research. One of these drugs, lovastatin, has been shown to increase learning in mice, but no comparable work has been done with flies. Ms. Vose proposes that treating flies with lovastatin and other approved drugs will improve their learning ability. If these experiments are successful, the Nf1 mutant flies can be used to screen for other useful drugs and novel compounds which can be further tested in mice and eventually clinical trials in humans suffering from this disease.

2007 Young Investigator Award Recipients

POSTDOCTORAL AWARDEES

Sheila Alcantara, MD: The University of Texas Southwestern Medical Center at Dallas
The role of neural stem cells in cancer: Cell of origin and cancer stem cells in gliomas
Glioma is one of the most severe NF1 manifestations. This project’s objective is to determine the role of neural/stem progenitor cells in initiation, development and progression of gliomas. These studies are going to use conditional knockout mice harboring mutations in p53, a tumor suppressor gene, and the neurofibromatosis gene Nf1, which develop gliomas with full penetrance. This work will attempt to shed more light on the roles of stem cells and stem cell-like cancer cells in the pathogenesis of NF1 gliomas.

Mateusz Kolanczyk, Ph.D.: Max Planck Institute for Molecular Genetics
Role of FGF signaling in the genesis of multiple bone phenotypes in NF1Prx1 mouse
Fifty per cent of NF1 patients develop bone abnormalities. The project focuses on elucidating the role of NF1 in the bone abnormalities observed in NF1 patients. The study is using a mouse model where Nf1 gene is inactivated in undifferentiated mesenchymal cells of limb buds, the NF1Prx1 mouse. Similar to NF1 patients, these mice show bowing of the tibia and diminished growth. Based on evidence that Fibroblast Growth Factor Receptors (FGFRs) are involved in bone abnormalities, the project attempts to exploit the FGFR signaling contribution in the NF1Prx1 phenotype. It is hoped that this study will provide information on the role of FGFRs in the NF1 bone abnormalities and by using FGFR specific inhibitors to identify new therapeutic targets.

Da Yond Lee, Ph.D.: Washington University
The differential impact of NF1 loss on brain region-specific neural stem cells
Though individuals with NF1 can develop tumors in a variety of brain regions, a significant proportion of NF1 brain tumors are specifically optic gliomas. . The project’s hypothesis is that the development of tumors in the optic nerve in children with NF1 reflects unique biological properties of the optic nerve neural stem cells conferred by Nf1 loss. The project aims to exploit further and characterize the biological properties of neural stem cells from different brain regions and to determine the impact of Nf1 loss on brain neural stem cell biological properties. The identification of the specific cell types that give rise to tumors in children with NF1 can lead to identification of novel therapeutic targets.

Okay Saydam, Ph.D.: Massachusetts General Hospital
Targeting microRNA regulation of meningioma growth
This project attempts to identify previously unknown pathways critical to NF2 meningioma and provide new therapeutic targets. In recent years, a class of small molecules called microRNAs (miRNAs) has been identified and has been shown to play crucial role in cancer. These studies propose to compare the miRNAs between cells derived from meningioma tumors and normal cells. Further characterization on significant miRNAs can shed light on the mechanisms of meningioma formation.

Weixi Wang, Ph.D.: Vanderbilt University
Bone pseudoarthrosis and fracture healing associated with neurofibromatosis
Five per cent of babies affected by NF1 suffer from bowing of the tibia and as a result bone fractures do not heal properly, leading to prolonged immobilization, recurrent fractures and in most severe cases amputation. This study proposes to generate a mouse model where Nf1 gene is absent from osteoblasts and characterize the process of healing following tibia fracture. In the second part of these studies, candidate drugs will be used to treat osteoblasts derived from the NF1 mouse model. It is hoped that these studies will reveal the role of NF1 in bone abnormities and propose new therapies.

Sybil M. Genther Williams, Ph.D.: Brigham and Women’s Hospital
Investigating the signals that restrict neurofibromas to a benign state or promote progression to malignancy
This project is exploiting the signals that restrict NF1 tumors to a benign state or promote the progression to malignancy. The lab has shown previously that loss of NF1 leads to immortalization or senescence depending on the cell type. It is suggested that senescence can be a mechanism of tumor suppression and by elucidating the cell signals that are involved in the protection from senescence can provide information how benign tumors progress to malignancy. Identification of these signals can provide new targets for potential therapies and can help tumors remaining in the benign state without progressing to malignancy.

PRE-DOCTORAL AWARDEES

Geoffrey Kilili: Tufts New England Medical Center
Negative regulation of MAPK signaling complexes by merlin
This project is going to study the role of merlin, the product of the Nf2 gene, in the activation of the ERK pathway and the increased proliferation rate observed in Nf2 knockout cells. The project’s hypothesis is that a number of signaling molecules including MLK3, the Rafs, and MSt2 exist in a multi-protein complex that promotes cell proliferation and inhibit cell death. Merlin, by sequestering MLK3 and release of Mst2 dissociates the complex, impairing ERK activation and promoting Mst2 activation and consequent inhibition of cell proliferation/survival. This project attempts to exploit further the complicated signaling pathways merlin is involved.

Brian S. Schmutzler: Indiana University
Glial Cell-Line Derived Neurotrophic Factor (GDNF) family molecules modulate sensory neuron sensititvity in Nf1+/- mice
A significant aspect of NF1 is the abnormally painful sensations patients experience. It is believed that this pain is due to inflammation related to increased inflammatory mediators. Certain growth factors can play the role of the inflammatory mediators and their production is increased in the Schwann cells of NF1 mouse models. It has been shown Nerve Growth Factor (NGF) and Glial cell line Derived Neurotrophic Factor (GDNF) increase sensitivity of the sensory neurons within and near the neurofibroma. The project’s hypothesis is that GDNF family molecules alter sensory neuron sensitivity, especially in the NF1 mouse model. This study will use behavioral pain models, and by measuring neuropetide transmitter release from neurons in culture will attempt to determine the role of NF1 in pain.

Matthew Wood: Dartmouth Medical School
Analysis of genomic instability following NF1 loss using S. cerevisiae as a model system
This study will exploit the mechanisms that contribute to plexiform neurofibroma degeneration to malignant peripheral nerve sheath tumors. This research will use budding yeast, a eukaryotic organism, which has similar proteins to NF1 and signaling pathways to humans. By unraveling the role of NF1 in DNA damage, this research may provide information on how plexiform neurofibromas evolve to malignant tumors and identify new targets for therapy.

2006 Young Investigator Award Recipients

POSTDOCTORAL AWARDEES

Jessica Casaletto, Ph.D.: Harvard Medical School/Massachusetts General Hospital
Role of Merlin and Ezrin in Junctional Remodeling during Tumorigenesis and Metastasis
This project addresses an important area of NF2 research: the relationship between merlin and the related ERM (Ezrin, Radixin, Moesin) proteins in epithelial tissues. Merlin is closely related to the ERM proteins, which localize to the cell membrane and regions of cell-cell contact, indicating roles in cell-cell communication. This project will study the balance of relationship between Merlin and Ezrin in morphogenesis and tumor progression. These studies will use Nf2 mutant mice and cells and will help to broaden our knowledge of the nature and function of merlin protein, which is essential in making progress toward developing therapeutics for NF2.

Chengkai Dai, Ph.D.: Massachusetts Institute of Technology
Role of Heat Shock Factor 1 (Hsf1) in modifying NF1-assiociated tumorigenesis
Given that NF1 is a progressive disease with a wide variability of clinical manifestations, it is likely that factors in addition to Nf1 gene mutations might profoundly modify the disease outcome. To provide better treatments and prognosis for NF1, it is important to identify those potential factors and understand the underlying mechanisms. This research is investigating the potential role in NF1 for Hsf1, a ‘master regulator’ of stress response in human disease and a crucial candidate modifier of tumor formation. It is hoped that these studies will provide not only basic mechanistic insights into how Hsf1 impacts NF1 disease outcomes, but also that they will be the basis for developing novel Hsf1-targeted therapeutics for NF1.

Ernesto Diaz-Flores, Ph.D.: University of California, San Francisco
Dissecting aberrant ras signaling induced by NF1 inactivation in myeloid disease
Clinical manifestations of NF1 include pediatric leukemias for which there are no effective current treatments. This research will use mouse models of Nf1- associated myeloid malignancies to study & uncover the signaling pathways alterations that contribute to these malignancies. This research will also use these models to address how inhibiting specific targets might represent candidate therapeutic approaches. This research will inform rational approaches to drug discovery and treatment, and potentially help to develop therapies for a broad range of NF1-derived tumors, as well as for myeloproliferative diseases and acute leukemia.

Cory Johannessen, Ph.D.: Harvard Medical School/Brigham & Women’s Hospital
Inhibition of the mTOR pathway as a therapy for NF1
The Nf1 gene product neurofibromin is a negative regulator of Ras (an important modulator of cell growth). However when neurofibromin is dysfunctional as it is in NF1, the precise pathways downstream of Ras that cause the clinical manifestations associated with NF1 are unclear. One of these, the mTOR pathway, is hyperactivated in tumor cells from patients with NF1. This research program will utilize mouse models of NF1 to explore mTOR inhibition as a therapeutic approach to treatment of NF1 tumors.

Jeong-Soo Lee, Ph.D.: Harvard University
Modeling NF1 and identifying its modifier using Zebrafish
Zebrafish are widely used to study genetic diseases & disorders. Unique advantages of zebrafish are the fact that they are easy to breed and study, and that many zebrafish genes are known to be similar in structure & function to human genes, so research findings from zebrafish can readily be translated to humans. This research project will be the first to study NF1 in zebrafish.

Zebrafish with mutations or blocked function in the Nf1 gene will be generated, to model the loss of gene function in NF1 patients. Mutant zebrafish will be analyzed to see which part of the NF1 protein is responsible for specific pathological abnormalities in different tissue types, and to begin to understand how the loss of NF1 results in such diverse symptoms in different NF1 patients. It will include a ‘modifier screen’ to help understand the complex molecular pathways controlled by the Nf1 gene, and identify new potential drug targets that can be used for the development of candidate NF1 therapeutics.

PRE-DOCTORAL AWARDEES

Monica Buchanan (Ph.D. candidate): Baylor College of Medicine
Localization of NF1-dependent learning in drosophila
This research project will study NF1-associated learning disabilities using Drosophila melanogaster - the fruit fly - as a model. The fruit fly is a widely used genetic model, and has previously been demonstrated as a useful model for such study of NF1-associated behavioral changes. The fly Nf1 gene is very similar to the human Nf1 gene, and genetically modified flies with disruptions in the Nf1 gene can readily be generated. A battery of meaningful behavioral tests can be used to test the behavioral impact on the flies of genetic modifications to the Nf1 gene. These studies will help to unravel the molecular processes involved in learning and memory and how these are impacted by individual Nf1 gene mutations.

Angela Hadjipanayis (Ph.D. candidate): University of Florida
Juvenile myelomonocytic leukemia (JMML) and other leukemias can affect children with NF1
JMML and related leukemias seen in NF1 are usually fatal. As is the case with NF1 solid tumors, there is a great need for therapeutics that can target the tumor cells without harming normal cells. This project is investigating a new gene that might be involved in the causal events of NF1 related leukemias. By unraveling this gene’s function in human leukemia samples and NF1 mouse and cell models, this research might offers a new target for developing better therapies for JMML and related leukemias, and potentially other NF1-related tumors.

Georgette Jones (Ph.D. candidate): Ohio State University
Investigating a role for The Carney Complex Gene PRKAR1A in NF1 and NF2 tumor formation
Schwann cells support and insulate nerve fibers throughout the body. However in NF1 and NF2, Schwann cells can give rise to schwannomas. These are usually benign but can become malignant. Schwannomas are also a feature of Carney Complex (CNC), which is caused by mutations in the gene PRKAR1A, an important regulator of the Protein Kinase A (PKA) pathway. This research will explore whether PRKAR1A also regulates schwannomas in NF1 and NF2. Tumors from a Prkar1a mouse model will be compared to NF1 and NF2 schwannomas. Interactions between PKA, neurofibromin and merlin will be studied. These studies could shed further light on the mechanisms of Schwann cell derived tumors in NF1 and NF2; demonstrate a role for PKA signaling pathway in NF1 or NF2; and delineate PKA as a candidate drug target for the treatment ofNF1 and NF2.