1991 — 1993 |
Mardon, Graeme |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Genetic Analysis of Retina Development in Drosphila @ University of California Berkeley |
0.912 |
1996 — 1999 |
Mardon, Graeme |
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. |
Retina Cell Fate Determination and Pattern Formation @ Baylor College of Medicine |
1 |
1998 — 2005 |
Mardon, Graeme |
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. |
Genetic Control of Retina Specification @ Baylor College of Medicine
[unreadable] DESCRIPTION (provided by applicant): Generating new tools for the prevention, diagnosis, and treatment of retinal diseases requires an increased understanding of the molecular mechanisms of retinal cell fate determination and differentiation. The goal of this competing renewal is to determine the function of the highly conserved mammalian Dach genes during retinal development and in adults. Both mice and humans possess two homologs of the Drosophila gene dachshund, which encodes a novel transcriptional cofactor that is both necessary and sufficient for retinal development in Drosophila. Mouse homologs of dachshund, named Dach1 and Dach2, are expressed in the retina during embryonic and postnatal life. In addition, Dach1 expression is dependent upon Math5, which encodes a DNA-binding transcription factor that is required for ganglion cell specification. We hypothesize that the Dach genes are required for normal retinal development. Although Dach1 null mutants die at birth with no obvious retinal phenotype, analysis later during development is precluded by neonatal lethality. Thus Dach1 may play a late role during eye development or there may be functional redundancy with Dach2. To further explore this possibility and to help elucidate the molecular mechanisms of retinal cell fate control, we will create conditional alleles of both genes using the Cre/loxP system. We propose the following Specific Aims: [unreadable] [unreadable] 1. Analyze Dach1 function during postnatal retinal development.2. Determine the role of Dach2 function during embryonic and postnatal retinal development.3. Place Dach1 and Dach2 in a retinal hierarchy with Pax6, Math5, and Brn3b. [unreadable] [unreadable] These studies are required to characterize the relationships between genes operating during retinal development. A greater understanding of these pathways is essential to our understanding of eye disease. Since our approach focuses on vertebrate homologues of the Drosophila gene dachshund, which is both necessary and sufficient for eye development, it is likely that uncovering the similarities and differences in retinal specification pathways is a key to the future development of diagnostic and therapeutic tools.
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1 |
2000 — 2019 |
Mardon, Graeme |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Molecular Genetics Emphasizing Vision Research @ Baylor College of Medicine
[unreadable] DESCRIPTION (provided by applicant): This is a resubmission of a competing renewal application for continued support for a training grant in molecular genetics emphasizing vision research at Baylor College of Medicine. At the time of the last renewal, the program was awarded six pre- and two postdoctoral positions and we are requesting a continuation of the same number of slots. The goal of this proposal is to provide comprehensive training to predoctoral students and postdoctoral fellows in both molecular genetics and visual processes in preparation for careers in vision research. There are 17 training faculty, including Full, Associate, and Assistant Professors. These faculty maintain independent, well-funded laboratories conducting research in both genetics and visual processes. Major areas of research include the molecular genetics of human eye disease, studies of fundamental retinal processes using the mouse, zebrafish, and Drosophila as model organisms, phototransduction, cataract formation, lens and corneal development, and glaucoma. All faculty on this grant actively use genetic techniques to pursue vision research and represent three institutions at the Texas Medical Center. Indeed, the highly interactive, multi-departmental and inter-institutional composition of our faculty is a key strength of our program. Student training comprises a full year of didactic and interactive coursework, journal clubs, and research rotations. In addition, we continue to offer a course entitled "Molecular Genetics in Vision Research" as well as a bi-monthly research seminar series, the "Houston Eye Club," in which graduate students and postdoctoral fellows present their work to a group about 30-40 researchers from more than a dozen vision research laboratories in Houston. Students are expected to remain on this grant for 2-4 years while fellows will usually be supported for 1-2 years during which time they are expected to apply for extramural funding. Predoctoral fellows are also advised and encouraged to apply for predoctoral fellowships when possible. Currently, there are 320 graduate students and 151 postdoctoral fellows eligible for support in the departments associated with this training program. In the last 10 years, 11 graduate students supported by this training grant have received a Ph.D. degree and four of these have continued their careers in vision research. Of the five postdoctorals supported, four are still engaged in vision research. Since many visual system disorders are inherited and there have been recent and significant advances in applying gene therapy to treat retinal disease, training new scientists who are well versed in both genetics and vision research is a top priority of our training program. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2000 — 2019 |
Mardon, Graeme |
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. |
Retina Cell-Fate Determination and Pattern Formation @ Baylor College of Medicine
DESCRIPTION (Verbatim from applicant's abstract): The long-term goal of this project is to improve our ability to prevent, diagnose and treat human retinal diseases. Our experimental approach uses the fruit fly Drosophila melanogaster as an animal model system to identify and determine the function of conserved genes that are required for normal retinal cell fate determination and differentiation. Our studies have focused on a group of retinal determination (RD) genes that encode nuclear proteins that function together in complexes to control gene transcription and retinal cell fates. Each of the RD genes, including eyeless, eyes absent, sine oculis and dachshund, is highly conserved in mammals. We have shown that dachshund (dac) is both necessary and sufficient for normal retinal development in Drosophila. That is, in the absence of dac function, flies develop with no eyes. Moreover, targeted expression of dac leads to the induction of properly formed ectopic eyes on the antennae, legs and thorax. These ectopic eyes contain all of the cell types found in the normal fly eye. Thus, dac functions near the top of the genetic hierarchy controlling retinal development in Drosophila. Importantly, dac is highly conserved in mice and humans and is strongly expressed in the mouse neural retina throughout development. In addition, we are investigating how the highly conserved general signaling pathways, such as hedgehog and the TGFI3 homolog dpp, are integrated with the function of the RD genes to control patterning and cell fate determination in the retina. Our continuing studies on the molecular and genetic mechanisms of RD gene function are therefore important steps toward understanding normal retinal development in humans. In addition, we have isolated and are studying Drosophila homologs of two new vertebrate genes that are key players in retinal development. Our specific aims are to: (1) dissect dac regulatory elements and identify genes directly controlling dac expression; (2) conduct structure/function studies and genetic screens to decipher dac function; (3) integrate the hedgehog signaling pathway with the retinal determination network; and (4) analyze the function of new, conserved genes required for normal retinal development. These studies are designed to further elucidate the molecular and genetic mechanisms controlling retinal cell fate determination in Drosophila, the most powerful genetic model system available. Since all of the genes we study are highly conserved in humans, this work will directly impact our understanding of human retinal development.
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1 |
2009 — 2012 |
Mardon, Graeme |
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. |
Retinal Cell-Fate Determination and Pattern Formation @ Baylor College of Medicine
DESCRIPTION (provided by applicant): The eyes absent (eya) and sine oculis (so) genes in Drosophila are key components of the retinal determination (RD) network, which is essential for normal development in both flies and vertebrates. Eya functions both as a transcriptional coactivator and a protein phosphatase while so encodes a homeodomain transcription factor. Both genes are necessary and sufficient for retinal development in Drosophila. Moreover, the Eya and So proteins physically interact and act synergistically as a highly potent transcription complex that regulates development of several organ systems. Two highly conserved homologs of so, Six3 and Six6, are required for normal retinal development in vertebrates. In humans, mutations in EYA1 and SIX1 cause the autosomal dominant disorder known as BOR (branchio-oto-renal) syndrome, characterized by branchial arch abnormalities, hearing loss, and kidney defects. Despite their importance during mammalian development, the mechanism of Eya and So action remains incompletely understood. In addition, Eya and So directly regulate atonal and senseless, which are required for the first steps in photoreceptor cell differentiation and are highly conserved in mammals. Two other conserved transcriptional regulators required for normal retinal differentiation, Lozenge and Groucho, also appear to be directly regulated by So. Thus, Eya and So mediate the transition from determination to differentiation and thereby act at a critical junction in organogenesis. Our proposal focuses on understanding the role of these six genes in a well-characterized genetic system, the Drosophila eye. We will use a combination of genetics, genomics, and biochemistry to analyze the roles of Eya and So, as well as Ato, Sens, Lozenge, and Groucho, during retinal development. Since genetic pathways are often conserved and reiteratively used during organ formation across phylogeny, studying the development of simpler organisms can provide rapid and significant insight into human disease. PUBLIC HEALTH RELEVANCE: The main goal of this project is to understand how the eyes absent (eya) and sine oculis (so) genes act during eye development. Both genes are highly conserved from fruit flies to humans and are known to play essential roles in human development, including the eye. We will use the unparalleled power of Drosophila genetics to decipher the function of these important but poorly understood genes.
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1 |
2011 — 2017 |
Chen, Rui Mardon, Graeme |
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. |
Molecular Mechanisms of Human Retinal Disease @ Baylor College of Medicine
Project Summary The long-term goal of this project is to improve both the diagnoses and the treatments of Leber congenital amaurosis (LCA). LCA is a set of inherited, early onset retinopathies that affect about 1 in 50,000 in the general U.S. population and accounts for more than 5% of all retinal dystrophies. The molecular basis for LCA is heterogeneous with mutations in 22 different genes that have been associated with the disease. Strikingly, ciliopathy has been identified as one of the major causes of LCA with 25% of the known disease- causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently identified that Spata7, a ciliopathy gene, maintains a photoreceptor- specific transition zone (PSTZ), which is a specialized structure in photoreceptor connecting cilia and plays a critical role in protein trafficking. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel PSTZ zone in the connecting cilium of photoreceptor cells. Our Specific Aims are to: Specific Aim 1: Define and characterize two novel zones of the connecting cilium. Specific Aim 2. Determine the mechanism of SPATA7 action in RPGR complex assembly and function in the distal TZ of photoreceptor cilia. Specific Aim 3: Determine the role of Spata7 in PSTZ structure and function. Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.
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1 |
2012 — 2016 |
Chen, Rui Mardon, Graeme |
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. |
Genetics of Early Onset Retinal Diseases @ Baylor College of Medicine
Abstract The goal of this project is to identify novel genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children, will be identified by combining whole exome sequencing with genetic mapping. Mutations in known LCA genes account for about 63% of all cases in the European population, suggesting that many additional LCA genes remain to be identified. To identify additional LCA disease genes, we have collected 37 consanguineous families with recessive LCA from Saudi Arabia. Homozygosity mapping and known LCA disease gene sequencing suggests that 18 of these families carry novel mutations in multiple novel LCA disease loci. In addition, we have sequenced all 16 known LCA genes in a collection of over 600 patient samples and have identified 224 unrelated patients that likely carry mutations in novel LCA disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause LCA. In this proposal, we will identify the underlying mutations in these patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies. Our Specific Aims are to: 1. Perform positional cloning of disease genes in consanguineous LCA families 2. Identify novel LCA genes by whole exome sequencing of a 300-patient cohort 3. Continued enrollment and mutation analysis of LCA families Discovery of novel LCA genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in LCA disease genes also cause other retinal dystrophies, isolation of additional LCA disease genes will provide important insights into the molecular mechanisms underlying both LCA and retinal dystrophies in general.
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1 |
2014 — 2021 |
Anabwani, Gabriel Joloba, Moses Lutaakome Kekitiinwa, Adeodata Rukyalekere Mardon, Graeme Mpoloka, Sununguko Wata Nkomazana, Oathokwa Mooketsana |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Collaborative African Genomics Network (Cafgen) @ Botswana Baylor Child/Clincal Ctr/Excell
DESCRIPTION (provided by applicant): Advanced genetic and genomic technologies promise to transform our understanding and approach to human health and disease. Such genomic analyses are now common in Western populations of European descent. Studies of host genetic factors underlying long-term non-progressors of HIV infection have led to new therapies through the identification of loci that are important to in vivo control of virus pathogenicity. Similar stdies of host genetic factors influencing active TB infection have also identified important loci that could significantly impact the future development of more effective therapeutic and prophylactic strategies. Most of these studies were undertaken in non-African, adult populations, although there are more than 2 million new cases of HIV and HIV-TB in Sub-Saharan Africa every year, including more than half a million in children. HIV-infected children - who differ from their adult counterparts in their route of acquisition, clinical course, and pathophysiology - have been conspicuously absent, although they potentially have more to ultimately contribute and gain from therapeutic advances. The Collaborative African Genomics Network (CAfGEN) aims to redress this scientific imbalance by integrating genetic and genomics technologies to probe host factors that are important to the progression of HIV and HIV-TB infection in sub-Saharan African children. The network will incorporate five sites - the Botswana and the Uganda Children's Clinical Centers of Excellence will provide clinical expertise for patient recruitment; Makerere University and the University of Botswana will provide local molecular genetic expertise; and Baylor College of Medicine will provide access to genomics expertise and resources that will ultimately be transitioned to African researchers and institutions in a sustainable manner. The CAfGEN research agenda includes the recruitment of prospective and retrospective cohorts of HIV and HIV-TB infected children; the development of core genomic facilities for sample processing and storage; candidate gene re-sequencing, HLA allelotyping and whole-exome sequencing of patients at the extremes of HIV disease progression; and integrated genomic analyses of active TB progression and associated clinical outcomes using expression quantitative trait loci. These projects will be undertaken through an extensive training and career development plan that will also see significant upgrades in local genomics infrastructure, in so doing, CAfGEN will create a unique, highly synergistic African alliance that can contribute novel and important mechanistic insights to pediatric HIV and HIV-TB disease progression while establishing sustainable genomics technology, expertise, and capacity on the African continent.
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0.913 |
2014 — 2016 |
Anabwani, Gabriel Joloba, Moses Lutaakome Kekitiinwa, Adeodata Rukyalekere Mardon, Graeme Mpoloka, Sununguko Wata Nkomazana, Oathokwa Mooketsana |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Host Genetic Factors in Pediatric Hiv Disease Progression @ Botswana Baylor Child/Clincal Ctr/Excell |
0.913 |
2014 — 2016 |
Anabwani, Gabriel Joloba, Moses Lutaakome Kekitiinwa, Adeodata Rukyalekere Mardon, Graeme Mpoloka, Sununguko Wata Nkomazana, Oathokwa Mooketsana |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Mechanisms of Tb Disease Among Hiv-Infected Children @ Botswana Baylor Child/Clincal Ctr/Excell
An integrated genomic approach is a powerful way of identifying functionally important genes and pathways that mediate the progression to active TB in HIV co-infection. This molecular insight is critical to the future development of viable strategies and therapies aimed at minimizing the significant clinical impact of active TB disease in HIV co-infected children. This project will train local researchers in the use of newer RNA technologies and statistical analyses that will complement and extend the efforts of CAfGEN to build longterm, sustainable, local genomic capacity that runs the gamut from data production to analysis.
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0.913 |
2014 — 2016 |
Anabwani, Gabriel Joloba, Moses Lutaakome Kekitiinwa, Adeodata Rukyalekere Mardon, Graeme Mpoloka, Sununguko Wata Nkomazana, Oathokwa Mooketsana |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Phenotyping and Bioarchiving @ Botswana Baylor Child/Clincal Ctr/Excell |
0.913 |
2018 — 2021 |
Mardon, Graeme |
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. |
Molecular Mechanisms of Connecting Cilium Function in the Vertebrate Eye @ Baylor College of Medicine
Project Summary The long-term goal of this project is to improve our understanding of the molecular mechanisms of inherited retinal diseases (IRDs) and to develop personalized treatments. Strikingly, ciliopathies have been identified as one of the major causes of IRDs with 25% of the known disease-causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently discovered a novel subdomain of the photoreceptor connecting cilium (CC), named the photoreceptor- specific transition zone (PSTZ), which plays a critical role in CC stability and function. Establishment of the PSTZ depends on Spata7, a known LCA disease gene, and other members of the RPGR complex. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel structure in the connecting cilium of photoreceptor cells. Our Specific Aims are to: Specific Aim 1: Investigate the mechanism of PSTZ establishment Specific Aim 2: Determine the role of RPGR complex members in PSTZ structure and function Specific Aim 3: Determine the role of Spata7 in RPGR complex assembly and in establishment versus maintenance of CC structure and function Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.
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1 |