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High-probability grants
According to our matching algorithm, Iain T. Shepherd is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2004 — 2008 |
Shepherd, Iain T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of the Zebrafish Enteric Nervous System
Our long term goal is to understand how the vertebrate enteric nervous system (ENS) is specified and patterned during embryogenesis. Understanding the cellular and molecular processes involved in ENS formation will provide insights into how a complex structure, such as a nervous system arises, during development. Furthermore, our studies are of potential clinical importance in understanding the mechanisms and molecules that underlie pediatric conditions where the ENS fails to form correctly, such as Hirschsprung disease (HSCR). The ENS is derived from the neural crest, a multipotent population of cells that migrates from the neural tube along specific pathways to generate a wide variety of neural and non-neural tissues. Different axial populations of neural crest cells contribute to specific structures and tissues. In this proposal we will address where, when, and how ENS precursors are specified during embryogenesis. Our studies use the zebrafish due to the model system's cell biological, molecular and genetic strengths that are uniquely appropriate for our proposed experiments. Specifically, we aim to answer the following questions: 1) Do zebrafish enteric neural crest precursors arise from a distinct subset of vagal neural crest cells? We will determine the origin of the zebrafish ENS by lineage analysis. We will then investigate by cell transplantation the role of regulative interactions in specifying ENS precursor cell fate within the premigratory neural crest; 2) What gene is affected in the zebrafish ENS mutant, enema? We have identified several zebrafish mutants that have significant reductions in the number of enteric neurons. One of these mutants is enema another is lessen. We recently determined that lessen has a mutation in TRAP100. We will now identify the gene that is lesioned in enema that results in the mutant phenotype; 3) Which steps in ENS precursor development are affected in lessen and enema? We will characterize these mutants to determine cell biologically where, when, and how these mutations cause their phenotypes.Together the proposed aims will help increase our understanding of the mechanisms and molecules involved in generating the ENS and may provide valuable insights into the underlying causes of HSCR.
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1 |
2013 — 2014 |
Shepherd, Iain T |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Analysis of Hscr Patient Exome Sequence Data Using Zebrafish
PROJECT SUMMARY The goal of this project is to demonstrate that the zebrafish can be used to rapidly determine the functional significance of newly identified gene variants in Hirschsprung disease (HSCR) patients. HSCR is a pediatric condition where the enteric nervous system (ENS) fails to form properly. The disease occurs once in every 5,000 live births and occurs both familially and sparodically. HSCR is a classic multifactorial genetic disorder, and its genetic basis is only partly understood. So far, geneticists have identified 12 genes with mutations in HSCR patients. Of these genes, ret accounts for >80% of all known mutations. However the genetic basis of the disease in the vast majority of HSCR patients is unknown. Furthermore, there is a high degree of variability in the penetrance of the disease phenotype associated with mutations in the known HSCR genes. Recent studies have identified a ret susceptibility allele in an enhancer of intron 1 of the ret gene that appears to be a significant risk factor in developing the disease but it is not sufficient to cause HSCR on its own. We have developed the zebrafish as a model system to study ENS development. We have shown there is a strong evolutionary conservation in the genes required for ENS development from zebrafish to man. Nearly all of the known HSCR genes have been shown to be required for normal zebrafish ENS development. Significantly, we have shown that antisense knockdown of the zebrafish orthologue of ret leads to intestinal aganglionosis in the fish. In this exploratory proposal, we will utilize the zebrafish model system to functionally analyze HSCR patients gene variants as a method to identify new causative HSCR genes. The proposed study is based on a long-standing collaboration between the Shepherd and Hofstra labs and utilizes the unique resources available to the labs (the collection of 400 Dutch HSCR patient DNA samples) and the expertise found in both the Shepherd (Zebrafish ENS development) and Hofstra (Genetic basis of HSCR) labs. Aim1: Identify gene variants in HSCR patients. There is a need for gene discovery in HSCR patients whose disease is currently not assigned to a specific gene or genes. We will preform exome sequencing on a selected group of HSCR patients who have the highest probability of having a strong loss of function coding mutation in one or more genes not previously implicated in the disease. Aim 2: Assess the functional significance of 10 selected HSCR exome identified genes in zebrafish. We will clone and characterize the expression of zebrafish orthologues of the HSCR variant genes. We will then use anti-sense oligonucleotides to assess the effects of these genes on zebrafish ENS development either alone or in combination with ret mutations in order to test for epistasis. The proposed Aims will identify new genes or gene combinations that cause HSCR. This will benefit patients directly when they undergo genetic screening for the condition and will potentially offer scientists new targets for the development of novel therapies to treat HSCR.
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