David F. Bishop
- PROFESSOR Genetics and Genomic Sciences
- DNA Recombination
- Gene Regulation
- Gene Therapy
- Heme Proteins
- Human Genetics and Genetic Disorders
- Iron Metabolism
- Protein Structure/Function
- RNA Splicing & Processing
- Sequence Alignment
- Stem Cells
- Transcription Factors
- Transgenic Mice
B.A., Goshen College
Ph.D., Michigan State University
- Dr. Bishop is engaged in basic and translational research directed toward diagnosis, characterization, and therapy of the genetic disorders of heme biosynthesis (sideroblastic anemia and the porphyrias). In addition, he directs the institution's DNA sequencing and genotyping core facility. He currently serves on Mount Sinai's Appointments and Promotions Committee, the Financial Conflicts of Interest in Research Committee, Biosafety Committee, and the Committee for Small Awards. Dr. Bishop also has teaching roles in the Graduate School.
ResearchSpecific Clinical/Research Interests:
Heme biosynthesis; biochemical and molecular genetics; enzymology, sequencing, genotyping and bioinformatics
Current Students: Hasan Ali
Postdoctoral Fellows: Vassili Tchaikovskii, Luis Cunha, Sonia Clavero, Mert Sozen, Makiko Yasuda
Research Personnel: Gunkut Akar, Edith Gould
Summary of Research Studies:
The research interests of our laboratory are directed to an understanding of the molecular and medical genetics of heme biosynthesis and its regulation and control by the rate-limiting enzyme of the pathway, 5-aminolevulinate synthase (ALAS). Our discovery of the existence of erythroid and non-erythroid isozymes of ALAS, the cloning and sequencing of an erythroid tissue-specific gene, ALAS2, and its mapping to chromosome Xp11.21 led to our identification of ALAS2 as the defective gene in patients with X-linked sideroblastic anemia. This gene shares greater than 50 % amino acid identity with the housekeeping isozyme, ALAS1, indicating that they arose from gene duplication and divergence selected by different functional requirements. Characterization of the structure and function of these isozymes in health and disease provides a better understanding of this crucial step in heme biosynthesis. Structure-function correlations between ALAS2 mutations found in X-linked sideroblastic anemia are being analyzed with the goals of diagnostic and therapeutic advances in the treatment of this genetic disorder. Sugstrate and product analogs are being studied as possible agents for enzyme stabilization and therapeutic intervention as small molecule chaperones. We have demonstrated an increased frequency of coinheritance of the mutant alleles for the HFE gene defective in hereditary hemochromatosis, a disorder that, like XLSA, involves iron storage and consequent tissue damage. Coinheritance of HFE and ALAS2 mutations lead to particularly severe iron accumulation.
Studies with clinical collaborators are showing that simple blood donation (phlebotomy) is an effective treatment for the iron overload in patients with X-linked sideroblastic anemia. These clinical studies of this interesting hematological disorder provide unique training opportunities for individuals who desire to bridge clinical and basic research investigations. In liver, the housekeeping gene, ALAS1, is the rate-limiting enzyme of heme biosynthesis and is markedly elevated in activity in the Porphyrias, the human inborn errors of heme metabolism. The regulation of heme biosynthesis by ALAS1 is unique in that it is one of the few mammalian pathways controlled by negative feedback repression by its end-product, heme. We are conduction studies to determine if there are any human genetic disorders caused by mutations in the ALAS1 gene. We identified the second mutation in the ABC7 transporter gene, defective in the related disorder, X-linked sideroblastic anemia with ataxia. Future studies will focus on promoter regulation by trans-factors and the function of ABC7 in cytosolic iron/sulfur protein assembly.
Our laboratory is also interested in the development of tools for bioinformatics and has, in a collaborative project with the Department of Biostatistics, developed a set of computational algorithms that predicts putative functional regions of tissue-specific regulation in genomic sequences. In collaboration with Dr. RJ Desnick, we are investigating approaches to gene therapy of the porphyrias using mouse models and studies into the reaction mechanism of uroporphyrinogen synthase and hydroxymethyl bilane synthase.
Current Research Studies:
4/01/80 - 3/31/09:Studies of Porphyria and Human Heme Biosynthesis; NIH-NIDDK; The major goal of this project is to investigate the biochemistry and molecular genetics of the four cytosolic heme biosynthetic enzymes and their respective deficiency diseases.
01/01/09 - 12/31/11: Congenital Erythropoietic Porphyria: Evaluation of IPS Cells for Murine and Human Therapy; NY State - NYSTEM; The major goal of this application is to cure a genetic disease (Congenital Erythropoietic Porphyria; CEP) using reprogrammed and corrected adult CEP skin cells from our mouse model as proof-of-principle for future treatment of human patients. These studies will compare murine and human iPS-derived cells with their ES cell counterparts at the mRNA and protein levels.
Role: PI Approved, awaiting letter of start date.
4/01/09 - 3/31/10: Illumina Genome Analyzer II, NIH - NCRR; The major goal of this application is to purchase an Illumina Genome Analyzer II next generation DNA sequencer to enable high-throughput and whole genome-based DNA analysis in an institutional DNA sequencing/genotyping Core.
Role: PI Approved, awaiting funding award
Cunha L, Kuti M, Bishop DF, Mezei M, Zeng L, Zhou M, Desnick RJ. Human uroporphyrinogen III synthase: NMR-based mapping of the active site. Proteins: Structure, Function and Bioinformatics 2008; 71: 855-873.
Yasuda M, Domaradzki ME, Armentano D, Cheng SH, Bishop DF, Desnick RJ. Acute intermittent porphyria: vector optimization for gene therapy. J. Gen. Med 2007; 9: 806-811.
Bishop D, Johansson A, Phelps R, Shady AA, Ramirez MM, Yasuda M, Caro A, Desnick RJ. Uroporphyrinogen III synthase knock-in mice have the human erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions. Am J Hum Genet 2006; 78: 645-658.
Chan P, Gonzalez-Maeso J, Ruf F, Bishop D, Hof PR, Sealfon SC. Epsilon-sarcoglycan immunoreactivity and mRNA expression in mouse brain. J Comp Neurol 2005; 482: 50-73.
Solis C, Martinez-Bermejo A, Naidich TP, Kaufmann WE, Astrin KH, Bishop D, Desnick RJ. Acute intermittent porphyria: Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol 2004; 61: 1764-1770.
Bekri S, May A, Cotter PD, Al-Sabah AI, Guo X, Bishop DF. A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia. Blood 2003; 102: 698-704.
Cazzola M, May A, Bergamaschi G, Cerani P, Ferrillo S, Bishop DF. Absent phenotypic expression of X-linked sideroblastic anemia in one of two brothers with a novel ALAS2 mutation. Blood 2002 Dec 1; 100(12): 4236-4238.
Shady AA, Colby BR, Cunha LF, Astrin KH, Bishop DF, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene. Br J Haematol 2002; 117: 980-987.
Solis C, Aizencang GI, Astrin KH, Bishop DF, Desnick RJ. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest 2001; 107: 753-762.
Su X, Wallenstein S, Bishop DF. Non-overlapping clusters: Approximate distribution and application to molecular biology. Biometrics 2001; 57: 420-426.
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Below are financial relationships with industry reported by Dr. Bishop during 2012 and/or 2013. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
- Genzyme Corporation
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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