Michael A Bender, MD, PhD

Michael A Bender, MD, PhD

Specialties

"Imagine being born with a chronic disease where, out of the blue, you suddenly have episodes of excruciating pain. Since you appear “normal,” many people do not believe you and accuse you of just wanting pain medicine. This situation is complicated by racial biases and difficulties accessing healthcare for this disease (which receives less attention and fewer research dollars than other diseases, even though it is more common). Treating sickle cell disease involves cutting-edge molecular and cell biology as well as confronting issues of access to healthcare and community education in an underserved population. I am honored to work with families affected by sickle cell disease."

  • Biography

    M. A. Bender, MD, PhD, is attending physician at Seattle Children’s Hospital and director of Odessa Brown Comprehensive Sickle Cell Clinic; he is an associate professor at the University of Washington School of Medicine and has a research lab at the Fred Hutchinson Cancer Center.

    Clinically, Bender has a long-standing commitment to hemoglobinopathies with an emphasis on sickle cell disease, and special emphasis on patient education, community outreach and access to health care. He acts as a consultant to the state newborn screening program regarding hemoglobinopathies, providing advice to the state, community physicians and families. Bender has worked with the Puget Sound Blood Center’s Rare Blood Groups program to increase the number of minority donors by overcoming cultural barriers and improving education and information services, and he received the American Society of Hematology’s Champion for Advocacy award. He is member of the NIH Sickle Cell Disease Advisory Committee.

    His research focuses on regulation of the chromatin structure in vivo, using the beta-globin locus as a model. Bender is working on multiple projects, ranging from developing new techniques to analyze chromatin structure, to establishing a statewide collaborative to provide better support for patients, families, practitioners and community members affected by sickle cell disease. In order to test hypotheses’ as to how chromatin structure is regulated he has generated mice with deletions of DNase I hypersensitive sites (HSs) that mark putative regulatory regions of the beta-globin locus.   The largest of these deletes the control region (LCR), and results in changes in chromatin structure, expression, sub-nuclear localization and timing of DNA replication, raising the question of how these attributes are linked and coordinated.  The most prominent model for beta-globin gene activation proposes that the LCR and HSs flanking interact to form an “active chromatin hub” essential for high-level expression.  Systematic deletion of components of this hub suggest that this model is in fact not correct, and raising the questions 1) what is the function of these highly conserved regions, 2) what is necessary for activation of the locus and 3) how these mutations affect nuclear localization, chromatin structure and replication timing and how these attributes are linked.   For example, the nuclear periphery is associated with silenced genes, while the nuclear interior is associated with active gene expression.  Notably, with erythroid differentiation beta-globin expression increases and is associated with re-localization from the periphery to the central nucleoplasm, begging the question of if expression leads to re-localization, re-localization leads to activation of expression, or if these processes are regulated independently.  How these processes change with differentiation and the role of cis-acting elements is being determined.

    Board Certification(s)

    Pediatric Hematology-Oncology

    Education

    University of Washington School of Medicine, Seattle, WA

    Residency

    University of Washington School of Medicine, Seattle, WA

    Fellowship

    University of Washington School of Medicine, Seattle, WA

    Clinical Interests

    Hemoglobinopathies, newborn screening

    Research Description

    My research focuses on two main areas: regulation of the chromatin structure in vivo, using the beta-globin locus as a model; and the manipulation of the oxidation/reduction state in vivo to affect sickle cell disease.

    I am working on multiple research projects, ranging from developing new techniques to analyze chromatin structure, to establishing a statewide collaborative to provide better support for patients, families, practitioners and community members affected by sickle cell disease. Several strategies have been used to delete multiple DNaseI hypersensitive sites (HSs) of the beta-globin locus control region (LCR). The LCR is essential for the activation of the locus. Loss of the LCR decreases but does not eliminate expression, but does not lead to a major change in chromatin structure. As this is different than predicted from analysis of a human with an LCR deletion, two approaches were pursued. The first was to extend the deletion further upstream of the LCR. The second was to identify and delete additional candidate regulatory regions from the endogenous locus in mice. Data from several systems has implicated HSs ?anking the locus as being important in the regulation of chromatin structure and expression of the locus. Several models have been generated about the role of these regions. The results of these studies have been published and demonstrate the inaccuracy of several prior models for globin gene regulation. I am using long-range DNase sensitivity and chromatin immunoprecipitation studies to further characterize the region through erythroid development and generate new models.

    Research Focus Area

    Blood Disorders, Translational Research

  • Patient Testimonials

  • Awards and Honors

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  • Publications

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