Disease Models and Mechanisms (DMM) offers awards to bring together unique skill sets among researchers with an interest in model organisms of disease. DMM Travelling Fellowships encourage graduate students or postdocs to combine the expertise of their immediate colleagues with the technical or conceptual advancements of scientists outside of their laboratories. These awards offer up to £2500 (or currency equivalent) for collaborative visits to other laboratories. This money is intended to offset the expenses incurred through travel or other expenses related to initiating a new collaboration outside of the host lab institution.
Alleviating Parkinson’s disease symptoms using chemical chaperones
Parkinson’s disease (PD) is a devastating degenerative neurological disease affecting 1–2% of people over the age of 50. The clinical features of PD include motor impairments, such as resting tremor, bradykinesia, postural instability and rigidity, as well as non-motoric impairments. The causative molecular pathways are obscure, but may involve either environmental or genetic factors, or both.
Treatments for PD are limited and the disease remains progressive. The hallmark of PD is the loss of normal conformation of the α-synuclein protein in dopaminergic neurons, followed by its aggregation into toxic oligomers and fibrils known as Lewy bodies. The role of Lewy bodies in pathogenesis is unclear, but emerging data suggests that preventing α-synuclein misfolding and aggregation could inhibit the disease process and, thus, it is an attractive therapeutic approach. One approach is to use small molecules, called chemical chaperones, which are capable of crossing the blood-brain barrier (BBB), to promote the normal folding of the α-synuclein protein.
Moran Frenkel-Pinter from Prof. Segal’s and Prof. Gazit’s laboratories at the Tel-Aviv University in Israel is identifying compounds that prevent the neurotoxic aggregation of α-synuclein and alleviate disease symptoms in a Drosophila model of PD. Her collaboration with Prof. Masliah at the University of San Diego in the USA will expand this work to include mouse models of PD. Taken together, the use of Drosophila and mouse models of PD should provide a powerful system to examine the concept of using chemical chaperones for the prevention and treatment of PD, and possibly for treating neurodegenerative disorders in general.
Screening to reverse melanoma in zebrafish
Melanoma is the most serious form of skin cancer. It develops in skin cells that produce melanin and aggressively infiltrates body tissues, even with treatment. Patients with metastatic melanoma have a five-year mortality rate of nearly 70%. The cascade of events leading to the development and invasive characteristics of melanoma is still poorly understood. Progress in understanding the origin, nature and mechanisms of the disease should promote the development of more effective treatments.
The transparent zebrafish is an ideal system to study melanoma progression and they provide an inexpensive experimental assay platform for drug screening. Cristina Santoriello, who works in Dr Mione’s laboratory at the IFOM-IEO campus in Italy, developed a transgenic line of zebrafish that express oncogenic Ras driven by the kit promoter. The Ras-expressing fish develop melanomas at between one and three months of age. Transgenic larvae show an overpigmentation phenotype by just three days post-fertilization owing to an increased number and size of melanophores. In collaboration with Dr Kaufman and Dr Zon at the Children’s Hospital in Boston, Cristina will use the transgenic larvae to identify chemicals that can revert the abnormal growth and migration of transformed melanophores.
Tracing the origin of brain tumors
Intracranial pediatric germ cell tumors are an unusual class of brain tumor found predominantly in young infants or in teenagers. The prevailing theory is that these tumors arise from germ cell progenitors that aberrantly migrate from the gonadal area to the brain during embryogenesis. As with other types of brain tumors, they are associated with a number of side effects including edema, headaches, vomiting and visual problems. Some tumors require surgical excision, but many respond well to radiation therapy. However, all of the therapies have significant side effects, and their management and prognosis is largely determined by location and tumor histology.
Chris Tan studies at The University of Nottingham with Dr Paul Scotting, who suggests that intracranial pediatric germ cell tumors may actually arise from neural progenitors that normally reside in the developing brain. In collaboration with Dr Val Wilson, at the MRC Centre for Regenerative Medicine in Edinburgh, Chris will use transgenic mice to analyze the potential mechanism by which neural stem cells could become transformed into germ cell tumors. The aim is to provide clear evidence as to whether neural stem cells could indeed be the origin of this class of brain tumor. It is hoped that this study will provide a clear rationale to establish the first animal model in which to study this class of tumor.