Matthew Barber - US grants

DESCRIPTION (provided by applicant): Pelvic floor disorders (PFD) including urinary incontinence, pelvic organ prolapse (POP), and fecal incontinence affect a substantial proportion of women in the U.S. PFD result in significant psychosocial costs to an individual and their aggregate social and economic costs to society are enormous. Despite their substantial health impact, the quality of the evidence supporting most of the commonly used treatments, especially surgical interventions, is limited by the lack of standardization of diagnostic and therapeutic interventions, use of non-standardized and non-validated outcome measures, poor quality research designs, and inadequate power to detect clinically meaningful differences. The long-term objective of the Pelvic Floor Disorders Network (PFDN) is to identify optimum diagnosis and management strategies for women with PFD using the highest quality research methods available. The specific aims of this application are: 1) to demonstrate that the Cleveland Clinic Foundation (CCF) possesses the personnel, patient, clinical, and administrative resources needed for successful participation as a Clinical Site in the PFDN;and that our participation would be advantageous to the successful attainment of the Network's scientific goals and 2) to present a concept application for potential conduct by the PFDN. The broad, long-term objectives of our concept application are 1) to compare sacrospinous ligament fixation (SSLF) to uterosacral vaginal vault fixation (USWS) and 2) to assess the role of perioperative pelvic floor physiotherapy (PFPT) in women undergoing transvaginal surgery for apical or uterine POP. Our Specific aims are to: 1) compare the anatomic outcomes of SSLF to USWS in women undergoing transvaginal surgery for Stage 2-4 POP involving the vaginal apex or uterus 3 years after surgery;2) compare functional, sexual, and health-related quality of life (HRQOL) outcomes of SSLF to USWS in the same women 3 years after surgery;3) assess whether short-term functional, sexual, and HRQOL outcomes improve in women receiving PFPT perioperatively compared to those who receive surgery alone;4) assess whether perioperative PFPT improves anatomic, functional, sexual and HRQOL outcomes 3 years after surgery (long-term) compared to surgery alone and 5) determine the incremental cost-effectiveness of perioperative PFPT at the time of transvaginal surgery for POP. We present a collaborative multi-centered randomized trial comparing SSLF to USSVS with or without perioperative PFPT using a 2x2 factorial study design. A standardized common protocol for enrollment, treatment and data collection will be employed by 6-8 Clinical Sites within the PFDN coordinated by the data coordinating center.

DESCRIPTION (provided by applicant): The goal of the Pelvic Floor Disorders Network (PFDN) is to identify optimum diagnosis and management strategies for women with pelvic floor disorders (PFD) using the highest quality research methods available. The Cleveland Clinic offers a stable academic and research-oriented environment for the conduct of PFDN studies including experienced investigators with complementary clinical and research backgrounds that have a particular interest and a successful history of conducting clinical trials evaluating both surgical and nonsurgical therapies for women with PFD. The specific aims of this application are: 1) to demonstrate that the Cleveland Clinic (CC) Clinical Site has contributed substantially to the academic, administrative, and clinical aspects of the PFDN since joining in its 2nd 5-year cycle; that it possesses the personnel, patient, clinical and administrative resources needed for successful participation; and that continued participation would be advantageous to the successful attainment of the Network's scientific goals and 2) to present a concept proposal for potential conduct by the PFDN. We propose evaluating the comparative effectiveness of sacrospinous hysteropexy (SSH), the most well-studied uterine-sparing pelvic organ prolapse (POP) surgery, relative to total vaginal hysterectomy with sacrospinous ligament fixation (TVH/SSLF), a commonly used hysterectomy-based vaginal uterovaginal prolapse procedure. The specific aims of the concept proposal are: 1) compare the anatomic, functional, sexual and health-related quality of life outcomes of SSH to TVH/SSLF in women undergoing surgery for Stage 2-4 POP uterovaginal prolapse 2 years after surgery; 2) compare surgical recovery and short- and long-term morbidity of SSH and TVH/SSLF in these same women and 3) determine the incremental cost-effectiveness of SSH compared to TVH/SSLF for the treatment of Stage 2-4 POP. Enrolled subjects will be randomized in the operating room on the day of surgery to receive either SSH or TVH/SSLF (1:1) using a random permutated block design. Randomization will be stratified by surgeon to account for the varying experience and expertise. Subjects and study coordinators will be blinded to treatment assignment until completion of the study. RELEVANCE: Nearly one quarter of all women report symptoms of at least one PFD, including prolapse. POP is the most common indication for hysterectomy in postmenopausal women and it is unknown whether the addition of hysterectomy to POP surgery is integral to successful surgical outcome. The results of our concept proposal could justify or eliminate the need for as many as 70,000 hysterectomies in the US each year.

DESCRIPTION (provided by applicant): Preventing the acquisition of essential iron by pathogens is a critical component of innate immunity. Pathogenic bacteria have thus developed various strategies to scavenge iron from host proteins. While the importance of the battle for iron in infection is well appreciated, the evolutionary consequences for this conflict on host cellular pathways are unknown. In my preliminary work I have found that several iron sequestration genes, including the iron transporter transferrin, are rapidly evolving in primates. Notably, codons in transferrin undergoing rapid evolution map to interaction sites with bacterial transferrin receptors, suggesting that transferrin has adapted to thwart pathogen iron acquisition. For my proposal I will perform phylogenetic analyses of transferrin and bacterial receptors to identify sites and lineages subject to strong evolutionary pressure. I will also determine the functional consequences of transferrin adaptation by testing bacterial growth in the presence of diverse primate transferrin homologs. Finally, I will assess the trade-offs associated with pathogen- driven evolution on transferrin endogenous functions, including iron binding and interaction with human receptors. Together, this work will provide one of the first detailed analyses of a molecular arms race involving bacterial pathogens and shed light on how pathogens have shaped the evolution of a fundamental host cellular pathway.

? DESCRIPTION (provided by applicant): Evolutionary interactions between microbial pathogens and their hosts can mean the difference between a deadly pandemic and minor infection. The sequestration of iron and other micronutrients has recently emerged as a potent form of innate host defense termed nutritional immunity, which is actively counteracted by pathogen iron piracy to scavenge this nutrient from host proteins. While the molecular basis for these interactions have been established, the evolutionary implications of the battle for iron have not been previously investigated. I recently discovered that the primate iron transport protein transferrin has been engaged in a long- standing evolutionary conflict with TbpA, a bacterial surface receptor that targets transferrin as a nutrient iron source. Experimental evidence further indicates that transferrin evolution has played an important role during 40 million years of primate divergence and even in modern human populations. This proposal aims to complement my past training in biochemistry and evolutionary genetics with microbiology and genomic approaches to investigate mechanisms of bacterial pathogen evolution, using the transferrin-TbpA interface as a model system. During the K99 phase of this award I will investigate the functional consequences for rapid evolution in bacterial TbpA using molecular genetics as well as bacterial competition assays. This work will complement experimental evolution approaches using the transferrin-TbpA interface to study evolutionary trade-offs and pathogen host-range, work which I will carry forward into the independent R00 stage of the award. Together this proposal will lay the groundwork for an independent research program that integrates evolutionary genetics, biochemistry and microbiology to investigate the implications of host-pathogen evolution on human health and disease susceptibility.

The broad long-term objective of the NICHD Pelvic Floor Disorders Network (PFDN) is to perform multicenter research to study clinical and health aspects of pelvic floor disorders (PFD) with an emphasis on performing randomized clinical trials in order to reduce the burden of these conditions on women and their families. The Cleveland Clinic is seeking to successfully compete in the fourth cycle of the PFDN. The Cleveland Clinic PFDN Clinical Site joined the Network as one of its seven Clinical Sites at the beginning of the Network's 2nd 5- year cycle (2006) and has continued as a highly productive clinical site through its 2nd and 3rd cycles (2006- 2015). The specific aims of this application are to: 1) demonstrate that the Cleveland Clinic PFDN Site has contributed substantially to the academic, administrative, and clinical aspects of the PFDN during its 2nd and 3rd 5-year cycles; 2) demonstrate that we possess the personnel, patient, clinical and administrative resources needed for successful participation; and that our continued participation would be advantageous to the successful attainment of the Network's scientific goals, and 3) describe the unique strengths of the Cleveland Clinic Site relevant to PFD research. The Cleveland Clinic offers a stable, research-oriented environment for the conduct of Network studies includes highly experienced investigators with complementary clinical and research backgrounds with expertise in urogynecology, urology, colorectal surgery, physical therapy, epidemiology, radiology and biomedical engineering. Additionally, our site offers unique expertise in PFD outcome measure development and validation, development of clinical risk prediction models, and basic and translational research of PFDs. The Cleveland Clinic Center for Female Pelvic Medicine and Reconstructive Surgery provides care to a large volume of women with the full spectrum of PFD including urinary incontinence, fecal incontinence and pelvic organ prolapse and other sensory and emptying abnormalities of the lower urinary and gastrointestinal tracts with approximately 3,200 new patients seen and 3,900 surgeries performed annually. Our research team has a long and successful history of conducting clinical and translational research including clinical trials evaluating both surgical and non-surgical therapies for women with PFD. We have developed an infrastructure and environment conducive to the conduct of clinical studies of the PFDN and have made substantial contributions towards PFDN productivity including taking leadership in the design, implementation and publications of many PFDN studies and analyses. The unique strengths of the Cleveland Clinic Site have expanded and strengthened PFDN activities in the 2nd and 3rd cycle and will continue to be advantageous to the Network in the future. The health-relatedness of the PFDN and our application is that on-going and future Network studies will significantly advance the field by filling important gaps in our knowledge to expand evidence-based treatments for women with PFD.

Project Summary Microbes and their animal hosts encode numerous proteins to sense, manipulate, and defend against each other. The outcome of these interactions can mean the difference between a mutualistic exchange and a fatal infection. Epithelial surfaces provide the point of first contact between hosts and diverse communities of commensal bacteria, in addition to forming a critical barrier against bacterial pathogens. Although host and microbial proteins at these interfaces can evolve rapidly between and within populations, the impact of such diversity on immune defense is largely unknown. This proposal will leverage host-microbe barrier interactions as models to investigate the causes and consequences of adaptive protein evolution. We will first apply integrative phylogenetic and experimental approaches to determine how diversification of epithelial surface proteins mediates cell-cell adhesion and virulence of human-associated bacterial pathogens. In a second line of study, we will identify how evolution of primate secreted immunity proteins modulates bacterial destruction and defense functions. These projects will also employ experimental evolution in the laboratory to trace mechanisms of bacterial adaptation to antimicrobial enzymes in real time. This research program will advance our fundamental understanding of evolving host-microbe systems and accelerate strategies to diagnose and combat the growing threat of bacterial infectious disease.

PROGRAM SUMMARY/ABSTRACT The long-term goal of the Duke Women's Reproductive Health Research (WRHR) career development program is to develop a cohort of highly skilled obstetrician/gynecologist (Ob-Gyn) researchers with expertise in research methodology reinforced by an understanding of the resources, skills, and tools needed to build a successful long-lasting career as Ob-Gyn clinician-investigators. We will leverage deep Institutional and Departmental expertise, infrastructure and commitment to research career development to: (1) identify and recruit Scholars from diverse backgrounds and provide individualized mentoring and career development support in an environment of team science, (2) train this cohort of researchers by fostering state-of-the-art multidisciplinary research emphasizing the importance of diverse and innovative scientific methods, and (3) provide the skills and resources needed to lead their own multidisciplinary teams, ultimately becoming mentors for a new generation of clinician-investigators who will strengthen the field of Ob-Gyn. To achieve these aims, we have assembled a group of experienced mentors across 6 areas of excellence aligned with departmental and institutional expertise and priorities: 1) Reproductive Infectious Disease and Immunology; 2) Gynecologic Cancer; 3) Peri-conceptional Wellness and Early Human Development; 4) Pregnancy and Perinatology; 5) Pelvic Floor Disorders and 6) Innovative Research Methods. Two Scholars will be supported at any one time, with Scholars spending 2-5 years in mentored research training with a specific focus on topics relevant to the clinical practice of Ob-Gyn and its subspecialties. The Duke WRHR program builds on two successful existing K12 programs that are directed by experienced leadership in our department to create a dynamic career development program specifically for Ob-Gyns dedicated to women's reproductive health. The associated well- established infrastructure and tested approach to career development includes: creation of individualized career development plans, intense hands-on research on specific defined research projects, selection of a complimentary mentoring team, didactic course work, seminars, workshops, peer scholar group meetings, training in responsible conduct of research, and executive coaching to refine leadership skills. Scholar progress will be closely monitored by the Program Director and Research Director, as well as an Advisory Committee. We have built in mechanisms for feedback from both internal and external stakeholders and a novel evaluation plan to help the program better understand the gains experienced by Scholars. At the completion of the program, Scholars will be expected to have published their WRHR research in peer-reviewed journals and obtained independent funding. By building on the outstanding ongoing research relevant to women's reproductive health at Duke, the comprehensive career development resources available, and the Ob-Gyn department's track record in leading career development programs, the Duke WRHR program will create the next generation of research leaders in women's reproductive health.