Nancy C. Andrews - US grants

DESCRIPTION (provided by applicant): The Harvard-MIT MD-Ph.D. Program provides an integrated approach to educating physician-scientists who will become leaders in American medicine and biomedical research. In this program, students combine medical studies at Harvard Medical School with graduate studies at Harvard or MIT. The program offers students the largest collection of academic laboratories in the world for research training, complemented by teaching hospitals that are poised to rapidly translate basic discoveries into new clinical applications. Students choose between two medical education curricula: a hybrid learning approach that combines small-group teaching and problem-oriented learning with more traditional teaching methods (New Pathway), or a traditional curriculum with an emphasis on science and technology (Health Sciences and Technology). Both curricula include a set of rigorous clinical clerkships at the Harvard teaching hospitals. Students also choose from among the four graduate programs in the Division of Medical Sciences at Harvard Medical School, other graduate programs in the Harvard Graduate School of Arts and Sciences, and programs in the Graduate Schools of Science and Engineering at MIT. The medical and scientific training components are integrated throughout the program, beginning with a course in the Molecular Biology of Human Disease and a laboratory research rotation that are taken by all MSTP students during the summer before the first academic year. Although not all MD-Ph.D. students are awarded funding at the time of matriculation, the program is designed to include all students at Harvard Medical School who are simultaneously pursuing the MD and Ph.D. degrees. Unfunded students can enter the program at the time of enrollment in a Ph.D. program. The program provides academic and mentoring support to approximately 130 students, taking advantage of a large, committed faculty. Approximately 125 faculty members are directly involved with the program through service on program committees and/or participation as MD-Ph.D. student thesis advisors. Mentoring, advising, and all program activities are available both to students who are funded by MSTP and to students who are not. Other training grants, individual NIH investigator (R01) awards, individual student fellowships, departmental funds, hospital funds and unrestricted institutional funds are used to supplement MSTP student support.

DESCRIPTION (provided by applicant): Genetic hemochromatosis is a prevalent disorder of iron balance. The most common form of the disease results from mutations in HFE, an MHC class I protein of uncertain function. The goal of this proposal is to understand where and how the HFE protein normally functions to regulate iron homeostasis. To fully understand HFE, we feel that it is necessary to study iron homeostasis in living animals. We have taken a genetic approach to this problem, using transgenic mouse technology to alter individual components of iron transport and regulatory pathways, to determine how perturbation of one step alters iron balance. This application describes experiments for that purpose, and focuses on a new hypothesis: that HFE normally serves to modulate expression of hepcidin, a peptide hormone produced by the liver, and that hepcidin acts to attenuate release of iron from absorptive enterocytes and iron-recycling macrophages. In Aim 1, we will attempt to identify the cellular site of Hfe activity in vivo, by characterizing mice lacking the protein selectively in macrophages, hepatocytes or enterocytes. In Aim 2 we will investigate the importance of the interaction between Hfe and the transferrin receptor in vivo. In Aim 3, we will determine whether HFE is only involved in regulation of iron absorption in response to body iron stores, or whether it also participates in regulation in response to erythropoietic drive, hypoxia and inflammation. Finally, in Aim 4 we will explore the current model that hepcidin acts to attenuate release of iron from intestinal absorptive cells and macrophages. Together, these experiments should help to define the HFE/hepcidin regulatory axis, and inform future investigations of the pathogenesis of hemochromatosis.

DESCRIPTION (provided by applicant): Our laboratory has focused on discovering genes that are important for regulating iron homeostasis, with the overall goal of understanding human iron disorders. We have used animal models with inherited iron deficiency anemia to identify key components of iron transport pathways. We have also identified genes defective in human patients with inherited iron disorders. In the first cycle of this grant, we turned our attention to the discovery of novel genes that play more subtle roles in iron biology, reasoning that mouse genetics could be used as a tool not only to discover major components of iron transport and regulatory pathways, but also minor components that become important as modifiers of iron status. However, we still lack a complete understanding of genetic factors leading to variability in clinical presentations among human patients with iron disorders. The technology to carry out modifier gene mapping experiments has improved over the past five years, allowing novel approaches to this problem. This proposal describes two gene discovery experiments that will aid in the identification of additional candidate genes. Our overall hypothesis is that genes that modify iron stores in mice also modify the clinical expression of iron disorders in humans. Towards this end, we will (1) identify genes responsible for quantitative trait loci apparent in advanced intercross mouse lines with variable tissue iron content and (2) carry out genetic screens for novel genes involved in iron homeostasis using mice lacking Tmprss6, a key inhibitor of production of the iron regulatory hormone hepcidin. These complementary approaches should enhance our understanding of iron homeostasis and, importantly, yield new candidates for genes that determine clinical variability in the incidence and severity of iron disorders. PUBLIC HEALTH RELEVANCE: Iron overload and iron deficiency disorders are common in human populations. There is strong evidence that genetic factors influence which individuals are most severely affected. This application proposes two complementary approaches to identify those genetic factors, taking advantage of striking similarities in iron metabolism between humans and mice. Completion of this work should aid us in predicting which patients will need aggressive therapy and which can be managed conservatively

DESCRIPTION (provided by applicant): Duke University is committed to scientific research and its translation to improve human health, including through appropriate use of animals in research. Duke researchers whose current or past investigations have required significant use of USDA-covered species are responsible for $20,407,773 in annual direct costs from the National Institutes of Health. Strength of these programs is projected to double the need for large animal species by 2016, and current demand already exceeds capacity. To expand, modernize and centralize housing and procedural space for USDA-covered species, to meet current and projected research needs with these species, and to enable backfill of vacated spaces, construction of a two-story addition of 19,215 gross sf (gsf) (16,763 net sf, 87% efficiency), to Duke's existing Central Vivarium is proposed. The addition will include non-human primate housing and procedure space on the first floor (8,423 nsf) and large animal housing and procedure space on the second floor (8,340 nsf).The addition will allow consolidation of USDA-covered species within this single vivarium, while facilitating sharing of specialized equipment and enhancing security. Purpose-built for USDA-covered species, the addition will be designed to be flexible to maximize its usefulness as research needs evolve in coming years. The design also maximizes the addition's impact on research by utilizing existing cagewashing, support and surgical facilities. Contiguous with the existing Central Vivarium and Surgical Pavilion, the addition will be incorporated seamlessly into the veterinary, animal care, and administrative structure of Duke's Division of Laboratory Animal Resources. Planning for this addition was started in 2007 and halted in 2008 due to the economy. Duke already cannot accommodate current faculty needs for non-human primates, agricultural animals, and canines, and space constraints for these species have precluded recruitment of faculty who rely on these models. Furthermore, Duke investigators with promising findings and translational advances in neurobiology, movement disorders, surgery, transplantation, cardiovascular disease, infectious disease, and other fields are unable to accelerate translation or expand the scope of their research due to central housing constraints and limited procedural space for USDA-covered species. In addition, Duke's vivaria cannot support studies conducted under Good Laboratory Practice (GLP) regulations, restricting investigators'ability to conduct safety and toxicity studies in-house prior to submitting regulatory dossiers to the Food and Drug Admin. These problems are exacerbated by suboptimal design of the currently used space that makes routine husbandry, care, and monitoring of these species inefficient. The proposed project will rectify these existing problems, and in doing so will accelerate discovery and translation, provide state-of-the-art space for basic, translational, and pre-clinical studies, and create near-term and long-term jobs. In keeping with Duke's commitment to sustainability, the addition will meet requirements for LEED certification.

DESCRIPTION (provided by applicant): Transferrin receptor 1 (Tfr1) is a widely expressed protein that mediates cellular iron uptake through receptor-mediated endocytosis of Fe-transferrin. Tfr1-/- embryos die in mid-gestation from ineffective erythropoiesis, precluding assessment of roles of Tfr1 later in development and after birth. To determine whether Tfr1 is important in other tissues, we developed a conditional (floxed) Tfr1 mouse model that allows for inactivation of the Tfr1 gene in cells expressing transgenic Cre recombinase from tissue- specific promoters. We focused on skeletal and cardiac muscle because both tissues are highly metabolic and require iron for myoglobin production, mitochondrial biogenesis and mitochondrial function. Our preliminary results indicate that Tfr1 is critically important in both skeletal muscle and heart, and suggest an unanticipated link between iron homeostasis and energy metabolism. In our first Aim, we will characterize a severe phenotype observed in mice lacking Tfr1 in skeletal muscle, to understand how Tfr1 and iron transport contribute to muscle development, muscle iron homeostasis, mitochondrial biogenesis and regulation of energy metabolism. In our second Aim, we will perform similar studies to elucidate the role of Tfr1 in the heart, an organ in which iron balance must be tightly regulated to maintain constant, high-level function while avoiding deleterious effects of iron deficiency and iron overload.

7. Project Summary/Abstract Duke University, a research intensive institution, and North Carolina Central University (NCCU), a historically black institution, have united to provide career development of junior faculty with the goal to develop independent investigators who will benefit the health of women and advance our knowledge of sex/gender influences on health through interdisciplinary research. The Duke/NCCU BIRCWH is a strong, vibrant program that continues to have the leadership and institutional commitment for continued success. We request competitive renewal of our BIRCWH program, which has three major goals: 1) To develop highly skilled, innovative junior researchers investigating women's health and sex/gender elements of health and disease across a woman's lifespan through the use of interdisciplinary approaches; 2) To foster diversity in women's health and health disparities research by identifying and recruiting scholars from diverse backgrounds and by providing individualized mentoring and career development support in an environment of team science; 3) To encourage interdisciplinary research on all aspects of women's health by emphasizing the merits of all scientific categories and methods. Our program is built around three pillars: interdisciplinary research, structured mentoring, and individualized career development. The partnership between Duke and NCCU strengthens our goal of training minority scholars and focus on health care disparity. During our past funding periods, we have supported 21 BIRCWH Scholars, including 4 underrepresented minorities. Scholars and their expert interdisciplinary mentoring teams are making strong contributions to women's health research with particular focus on a) obesity, nutrition and cardiovascular health; b) pregnancy-related conditions, c) health services research, and d) breast and gynecological cancers. At any one time, we plan to support three junior faculty members (with one minority or NCCU scholar) from basic or clinical science backgrounds. Scholars choose a BIRCWH mentor from a core group of nationally known senior investigators from Duke and NCCU. Additional mentors are chosen to maximize interdisciplinary opportunities and collaborations. The career development program spans two to five years depending on the Scholar's educational needs and consists of intense hands-on research, mentoring, seminars, training in responsible conduct of research and didactic course work. At the completion of the program the Scholars are expected to have published their results in peer-reviewed journals and obtained funding as a Principal Investigator. Scholars' progress is monitored by the Leadership Team and the Internal Advisory Board (IAB). The program is evaluated and advised by the IAB and an External Advisory Board. We have also added formal external evaluations by an independent evaluator in the Duke Social Science Research Institute. Thus, the Duke/NCCU BIRCWH program will increase the availability of a diverse pool of highly trained women's health researchers to address the Nation's biomedical, behavioral, and clinical needs.