SIPID - Functional Genomics of Blood Disorders

Mentoring is the single most important factor that contributes to academic success. Those with mentors are more likely to make timely progress toward their degrees, and make renewed commitments to their professions. This collaboration allows mentees to meet the various challenges of their careers. Mentoring is a personal as well as a professional relationship.

Responsibilities of Mentors

The Mentor’s responsibilities include:

1. Providing leadership for the development of Mentee’s research project based on common interests;
2. Devote at least 5% effort towards interaction with mentee through regular communication by phone and/or email;
3. Assist with planning the mid-year visits to the Mentor’s laboratory;
4. The Mentor will also review grant and manuscript writing skills;
5. Mentee and Mentor will outline a strategy for developing grant application and plans for submission to NHLBI within 2 years of completing the SIPID program;
6. Establish long term collaborations with Mentees to increase the probability of a successful independent research career.

SIPID Mentors

John Cunningham, MD
Professor Cunningham’s laboratory is focused on the identification of tissue-specific transacting factor complexes that bind the globin gene promoters; characterization of such factors should permit the development of novel pharmacologic and/or gene therapeutic strategies to increase gamma-gene expression significantly. Application of such approaches in a clinical setting would result in the achievement of a significant amelioration of severe beta-thalassemia and sickle cell disease. Dr. Cunningham has focused on two specific areas: 1) to determine the physiological role of the stage selector protein (SSP), an erythroid-specific complex that binds to the proximal gamma-promoter and recruits the locus control region in a competitive environment; 2) the molecular mechanisms of EKLF action at the β-globin promoter. These studies utilize a combination of biochemical and genetic approaches in murine, rhesus, and human cell line models.

James Douglas Engel, PhD
Professor Engel is the G. Carl Huber Professor of Developmental Biology and Chair, of Cell and Developmental Biology. His laboratory uses mouse molecular genetics to define the etiology human disease. Developmental regulation of the basal transcriptional apparatus is instructed through interactions mediated by specific transcription factors and accessory proteins; these in turn activate or repress specific cascades of developmental events leading to tissue and organ elaboration. Dr. Engel’s laboratory focuses on the regulation of development by several transcription factor families and how these molecules contribute to organogenesis.

Steven R. Goodman, PhD
Professor Goodman demonstrated the molecular basis of the irreversibly sickled cell (ISC) caused by reversible oxidative damage to actin, and diminished ubiquitination of spectrin. Recently, Dr. Goodman and colleagues have demonstrated that spectrin is a chimeric E2/E3 ubiquitin ligase which ubiquitinates itself and several other membrane skeletal proteins. The Goodman lab further demonstrated that ubiquitination regulates the dissociation of the spectrin-4.1-actin and spectrin-adducin actin ternary complex, and that this enzymatic activity is greatly diminished in sickle RBCs due to an altered redox status. More recently, Dr. Goodman and colleagues performed a complete study of the RBC membrane proteome by tandem mass spectrometry.

Carolyn Hoppe, MD

Dr. Hoppe is a clinical scientist with a focus in translational research related to genetic modifiers of stroke in sickle cell disease. She is also involved in research investigating the regulation of sickle cell phospholipid organization and stroke risk due to increased red cell-endothelial interaction and vascular damage. The results of this research will clarify the mechanisms that underly phosphotidyl serine exposure in sickle cell disease and may lead to novel treatment regimen. Dr. Hoppe serves as the Medical Director of the Children’s Hospital of Oakland Research Institute Hemoglobinopathy Laboratory and the California State Newborn Screening and Follow-up Program. Dr. Hoppe provides joint leadership for the Laboratory Diagnostics Center which serves as the central genotype-phenotype laboratory for the Comprehensive Sickle Cell Center - Collaborative Database Project.

 

Philippe Leboulch, MD
Dr. Leboulch’s laboratory has been at the forefront in the design of gene therapy vectors for many years. His group has published the first long-term correction of a genetic disease by gene therapy in an animal model. A major current undertaking of his laboratory is the design of safe and effective lentiviral vectors capable of achieving long-term correction of sickle cell disease and beta-thalassemia. This model also serves as one of the most interesting paradigms in the field of gene therapy because of the complexity of the genetic structures to be transferred into hematopoietic stem cells to achieve high, regulated beta-globin gene expression restricted to the red blood cell lineage. Dr. Leboulch has now tackled the prevention of potential adverse events in human stem cells that include recently led to the first worldwide approval of a Phase I/II human clinical trial utilizing a lentiviral vector for the gene therapy of a genetic disease. Another present interest of the laboratory is the control of somatic cell expansion by "reversible immortalization" mediated by site-specific recombination

 

Stephen Levene, PhD

Research in the Levene laboratory focuses on sequence-dependent DNA structure and the interactions of site-specific recombination proteins with their DNA targets. Site-specific recombination is an essential event in many biological processes that involve genomic rearrangements, including gene amplification and copy number control, viral and phage host specificity, retroviral integration, and the transposition of drug resistance genes.  The goal of this work is to determine the physical and chemical factors that govern the efficiency, product distribution, and DNA-sequence specificity of recombination.  They use computer modeling and simulation to examine the interplay of DNA structure and recombinase action. Dr. Levene teaches bioinformatics physical chemistry, molecular and cell biology and the biotechnology methods courses.

 

Mohandas Narla, DrSci
Professor Narla’s laboratory research is primarily focused on the structure of blood cell membranes and regulation of blood cell production. Biophysical, biochemical, and molecular biological techniques are being used to study the protein and lipid organization in normal and various pathologic red cells. The research work is being funded by four NIH grants for which Dr. Narla serves as Principal Investigator. One grant titled, "Rheological and Adherence Properties of Sickle Red Cells," deals with determining the contribution of altered rheological and adherence properties of sickle RBCs in the microcirculation. A second grant, titled "Red Cell Deformability In Vitro and Survival In Vivo" deals with defining the role of cellular deformability in premature red cell destruction. To compliment his outstanding research program, Dr. Narla has an excellent track record for student training as well. His expertise as a researcher, mentor and training track record will bring balance to the SCDRC-SIPID program.

Betty S. Pace, MD
Professor Pace has studied the developmental regulation of gamma globin gene expression for the past 15 years. Drug studies to understand the molecular mechanisms and transcription factors involved in gamma-gene activation is the main strategy used in the Pace lab. The Pace lab is currently involved in genome wide microarray studies to identify trans-factor required for the gamma to beta- globin switch. Dr. Pace has a strong training track record. Since starting her faculty position at USA in 1994, Dr. Pace has participated in student training continuously. Students from high school to post doctoral levels have received molecular biology training under her mentorship. She had served as major professor for 9 students at the master’s and PhD level and has mentored 6 postdoctoral fellows. The first two post docs are junior faculty at Harvard and USA. They will be invited to participate in the SIPID program, Dr. Ofori-Acquah has already indicated a desire to attend. Dr. Pace has a strong commitment to training underrepresented minorities exemplified by the large percentage receiving mentorship in her lab.

Kenneth Peterson, PhD
Professor Peterson’s laboratory is primarily involved in elucidating mechanisms related to hemoglobin switching. Research focused on the cis- and trans-control of human beta-like globin genes is in progress. Mechanisms underlying the developmental regulation of globin gene switching that are under analysis in the lab include: 1) the role of spatial gene order, 2) the function of the LCR DNAse I-hypersensitive sites, and 3) gamma-globin gene silencing and activation. Experimental systems involving the analysis of transgenic mice and cell lines produced with human b-globin locus yeast artificial chromosomes as transgenes have been developed in his lab. In addition, they have established unique cell lines from the bone marrow and fetal liver for use in a novel system to enforce dimerization of growth signal transduction monomers into a functional molecule, resulting in multi-potential cell lines that proliferate. These lines will be used to select for fetal globin trans-activator proteins and for screening small molecule inducers of gamma-globin gene expression in collaboration with Dr. Pace.

George Stamatoyannopoulos, MD, DrSci
Professor Stamatoyannopoulos is Head of the Division of Medical Genetics and Genome Sciences and Adjunct Professor of Pathology at the University of Washington; he is also Director of the Markey Molecular Medicine Center. Dr. Stamatoyannopoulos laboratory works on five areas: 1) the control of human globin genes during development and differentiation. 2) The development of treatments for sickle cell disease through pharmacologic induction of fetal hemoglobin. 3) The development of somatic gene therapy for ß chain hemoglobinopathies. 4) The identification and delineation of regulatory elements of the human genome. 5) The investigation of molecular genetics of Bronze Age populations inhabiting the Aegean basin. Dr. Stamatoyannopoulos is a world leader in globin gene regulation and has a long track record for mentoring successful independent investigators.

Marsha Treadwell, PhD

Dr. Treadwell is a clinical psychologist with a long-standing interest in sickle cell disease and translational research, with a primary focus on physiologic and psychological aspects of treatment and outcome. Dr. Treadwell uses a unique combination of community outreach and clinical research to impact treatment outcome in this painful disease. Dr. Treadwell is currently focusing her primary interests on patient-oriented, bio-behavioral research. She has a study underway to evaluate psychobiological reactivity as a robust predictor of sickle cell pain, defined as the rate of painful episodes and daily pain frequency and intensity. Dr. Treadwell is also working to build on existing generic quality of life instruments to develop a sickle cell disease specific instrument. Dr. Treadwell continues to work toward increasing awareness of hemoglobin traits and access to sickle cell trait testing and counseling, within the context of an overall focus on improved health and innovative program of provider education and support for patients and families in self-advocacy.