John O. DeLancey - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): Damage to the muscles, fasciae, and sphincters of the pelvic floor that occurs at the time of birth is one of, if not the most important cause of stress urinary incontinence (SUI). Incontinent women have an odds ratio of 11.2 for having had a vaginal delivery compared with continent controls, twice the rate for any other factor. The mechanisms by which vaginal delivery causes SUI, however, are not understood. This study aims to clarify how damage caused by birth results in SUI. These insights will improve strategies for incontinence treatment and prevention. SUI is associated with defects in a) the urethral support systems and b) the sphincteric control system. Neither type of damage alone, however, adequately explains the occurrence of SUI. The hypothesis posed here is that vaginal birth causes SUI through a combination of damage to these two systems. To test this hypothesis, a case-control design is proposed enrolling as cases primiparous women with stress incontinence (SI; n=80), persisting 6 months postpartum. Negative controls will be nulliparous continent women (NC; n=80), and Positive controls; primiparous continent women (PC; n=80) delivered vaginally. They will quantify urethral support and sphincteric function in each of these groups using ultrasound, levator strength measurements and urethral pressure studies. For analysis of primary hypotheses, these data will be used to: 1) Show that measurements of either urethral support or sphincteric function alone will predict less than 30% of SI cases. 2) Identify which combinations of the three support parameters, three sphincter parameters, and their interactions have at least an 80% probability of correct prediction of SI compared with PC or NC by using discriminant analysis. 3) Construct a predictive model for SUI using discriminant functions and classification trees to indicate the relative importance of support parameters, sphincter parameters, and their interactions. Secondary hypotheses concern anatomical abnormalities visible on MRI responsible for functional problems. This project is expected to show that: 1) Loss of support involves connective tissue breaks and/or loss of levator ani bulk measurable on MRI as decrease in size of the levator ani, and 2) Sphincteric weakness results from quantifiable loss of sphincter bulk in the smooth and striated sphincter muscles. Correlation between anatomic measurements and functional parameters listed in the primary hypotheses will determine the cause of functional abnormalities. Other aims include 1) Using biomechanical models they will construct and validate a computer model of the fetal head and pelvic floor to test hypotheses concerning mechanisms of injury responsible for sphincter and support damage occurring during vaginal birth. 2) This project should establish the priority of obstetrical parameters associated with SUI. The importance of this research lies in its providing insights about the specific functional and anatomical defects caused by vaginal birth. This knowledge should help in devising future injury prevention at birth and help form the basis for more rational treatment selection in women with stress incontinence.

The basic mechanisms responsible for development of pelvic organ prolapse (POP) are not established. It has long been hypothesize that levator ani (LA) muscle impairment is associated with POP but this hypothesis has not been tested. This case control study will test the Null Hypothesis that levator ani muscle structure and function are the same in women with pelvic organ prolapse (cases) and women with normal support (controls). We will study 150 Cases who will be women with pelvic organ prolapse that extends more than 1 cm below the hymenal ring and 150 asymptomatic Controls with proven normal support matched for age, parity and race. Women with prior treatment for POP will be excluded. Differences in LA structure and function between cases and controls will be sought. Tests of LA structure and function: Structural abnormalities in LA muscle anatomy will be quantified in high-resolution proton density MR images. LA strength will be measured at rest and during maximum muscle contraction. Aim I: Test the null hypotheses that there are no differences in the anatomical cross-sectional area of the pubovisceral portion of the LA as seen in MR images of cases and controls. Aim 2: Test the null hypothesis that there is no difference in LA muscle strength at rest or during maximal contraction function in cases compared to controls. Sub analyses of levator anatomy and strength based on the size and type of the prolapse as well as the presence or absence of stress incontinence will also be carried out. Analysis of covariates possibly contributing to prolapse including prior hysterectomy, obesity, estrogen status, heavy lifting, and prolapse family history will be performed. Aim 3: Test the null hypothesis that muscle cross-sectional area is not correlated with LA strength for either cases or controls. The importance of this research lies in its providing fundamental insights about the specific functional and anatomical defects present in women with POP that will lead to improved research in this common disease. This information will guide future research as well as helping to devising more rational treatment selection.

DESCRIPTION (provided by applicant): The prevalence of urinary incontinence is often reported to be lower in black women than in white women. Whether or not this is true has not been confirmed in population based studies of younger women. In addition, the reasons for this prevalence difference are also unknown. This proposed population based, cross-sectional study will test the null hypothesis that no difference exists in the overall prevalence of urinary incontinence in black and white women. A telephone survey concerning occurrence of urinary incontinence (UT) and factors possible associated with UT will be administered to a regional sample of 1000 white women and 1500 black women age 30-60 years. A sub-sample of 130 black and white stress urinary incontinent, 100 black and white urge incontinent and 100 black and white continent women will undergo clinical testing in the form of pelvic floor testing to quantify bladder and urethra function. This survey will achieve the following aims: Aim lA: Define the prevalence of urinary incontinence in black and white women. Aim 1B: Determine the prevalence of stress and urge incontinence in black and white women. Aim 2: Identify demographic and personal factors that might explain the prevalence differences between the races. The clinical testing will accomplish the following aim. Aim 3: Compare the urethral and pelvic floor function of black and white women and continent and incontinent women. The survey and clinical components combined will achieve the final aim. Aim 4: Identify both epidemiologic and clinical factors associated with urinary incontinence. This research will confirm the reported race differences in the prevalence of urinary incontinence. It will also identify which epidemiologic and clinical factors contribute to this difference. Knowledge of these factors can then provide the basis for risk factor identification and the development of preventive strategies appropriate to different racial groups.

DESCRIPTION (provided by applicant): This proposal seeks to improve care for the women who suffer the priority health conditions of urinary incontinence and pelvic organ prolapse. These problems arise due to women's unique role in giving birth and, therefore, occur much less often in men. Each year 3 million women deliver babies and 11 % of women need surgery for incontinence and prolapse. A lack of basic understanding of the mechanisms involved in these conditions and their implications for treatment impedes progress. We propose a SCOR to unite 5 existing multidisciplinary researchers and to add 4 new investigators to expedite development of new knowledge needed to improve treatment and prevention. Project 1, "Biomechanics" will test hypotheses concerning basic mechanisms of pelvic floor structure and function. It will analyze the mechanical arrangement and properties of the components of the pelvic floor as well as how vaginal birth damages their integrity. Project 2, "Clinical Mechanisms" will test continent and stress incontinent women to detect the unique failure of component parts that, singularly and in combinations, are associated with stress incontinence. Project 3, "Treatment Selection" will identify the effects of birth induced muscle damage in women with stress incontinence and from these data, build and test a model to determine which defects will predict success or failure of pelvic muscle treatment. Core A, Administrative/Human Subjects/Biostatistics core provides project support by recruiting subjects, compiling and analyzing data and protecting subject safety. In Core A, two study groups will be formed concerning 1) Gender Impact and 2) Basic Sciences Futures to discuss expanding the issues raised by this research. Core B, Measurement & Imaging will provide technical support for the projects along with integrated image analysis for 2 and 3 dimensional spatial data gathered across projects. This research will produce needed insights to help women with pelvic floor dysfunction.

DESCRIPTION (provided by applicant): The goal of our proposed research is to discover the anatomical failures that cause anterior compartment (AC) prolapse. AC prolapse is clinically manifest as the inter-related problems of cystocele and uterine prolapse. Emerging research suggests that AC prolapse involves four fascial failure sites: 1) apical descent, 2) transverse defects, 3) midline defects and 4) paravaginal defects. Muscle defects in the pubic portion of the levator ani (LAP) are also involved. In Years 06-09 we quantified the roles of factors 1, 2 and LAP defects and established their role in AC failure. A specific knowledge gap now concerns the role of factors 3 & 4 and how they combine with LAP to cause AC prolapse. The interactions between all 4 fascial failures and LAP defects in causing prolapse have also not been evaluated (AIMS 1 & 3). In years 06-09 we also discovered distortion in the structurally important paravaginal complex (PVC) that is associated with increased AC prolapse. The PVC includes the arcus tendineus fascia pelvis (ATFP), arcus tendineus levator ani (ATLA) and LAP. It is not known which of these structures are involved in the PVC distortion or why their structural failure increases prolapse (AIMS 2 & 3). In AIM 1 we will use novel techniques to create and measure MR-based models of AC anatomy at peak Valsalva to determine the relative contribution of factors 3 (midline defect) and 4 (paravaginal defect) to AC prolapse in 81 cases with anterior compartment prolapse and 72 matched normal controls. LAP cross sectional area (CSA) measures will be made using MR-based modeling techniques developed in the previous funding cycle. We will then establish the relative contributions of each of the 4 fascial failure sites and their interactions with LAP CSA. In AIM 2 we will identify the structural changes present in PVC distortion by making MR-based models of these structures in unique scans of 26 subjects with unilateral PVC distortion that allow the two fascial arches and LAP CSA in a distorted side to be compared with the same structures of a normal side in the same women. We will also make comparisons between 26 women with, and 26 women without bilateral distortion. In AIM 3 we will develop and refine the 3rd generation of our award-winning 3D finite element biomechanical model. We will test at least three hypotheses regarding the biomechanical consequences of the alterations found in AIMS 1 and 2 on the development of AC prolapse. We will then explore the propensity for prolapse progression based on a number of important biomechanical factors and their interactions. These results will provide critical insights needed to reduce operative failures by providing a more accurate understanding of the pathomechanics of AC prolapse.

DESCRIPTION (provided by applicant): Although it has been known for millennia that many young women who give birth vaginally will suffer from disabling pelvic organ prolapse later in their lifespan, the factors linking these two events remain a mystery. Of the 3 million women who deliver vaginally each year 300,000 or 1 in 10 will later require surgery for pelvic floor dysfunction due to their unique sex-determined role in reproduction. Our discovery of birth-induced levator ani muscle injury and its strong relationship to prolapse has identified a key connection between birth and prolapse. Ignorance of how birth-induced injury occurs and how it produces subsequent prolapse has blocked efforts to improve prevention and treatment. In this application we seek to continue SCOR support for our broadly interdisciplinary sex-differences research group representing 4 schools and 2 institutes. The group has won 10 awards in the last 4 years for our discoveries and now seeks funding to begin to translate these insights into improved prevention at birth and strategies for better treatment. Project I Birth Biomechanics will test hypotheses concerning basic mechanisms of levator ani injury during vaginal birth to identify specific situations that may increase or decrease injury risk. Project II Injury Extensio will determine whether minor clinically insignificant levator injury after first birth extends to a clinically significant tear during second birth. Because a second birth doubles the risk of genital prolapse, this event offers the opportunity of preventing injury and their sequelae later in life. Project III Muscle-Ligament Dynamics will establish the interaction between birth-related levator muscle injury and the properties of the uterovaginal supporting ligaments associated with prolapse. Core A Administrative/Human Subjects integrates and supports the interdisciplinary team and provides project support by recruiting subjects, compiling and analyzing data and protecting subject safety. Core B Biostatistics/Measurements provides statistical and technical support for the projects along with integrated analysis for 2- and 3-dimensional spatial data gathered across projects. It will prepare data for presentation, publication, subject safety analysis and eventually public use. Core C Translation/Mentorshipw\\\ foster insight dissemination and drive investigator development. This SCOR will produce translational insights to reduce the sex-determined consequences women suffer from their unique role in reproduction. It will establish the scientific basis for new strategies to improve treatment, identify important prevention opportunities, and train a new generation of researchers.

Core A will be responsible for the following four services to unify, support, and coordinate the 3 projects in this SCOR. Aim 1 Administration: Core A will provide administrative support to Projects 1, 2 and 3 for recruitment, subject scheduling, forms generation, IRB issues, organization and confidential filing. In addition, it will file group renewal reports, generate, manage and plan project budgets, schedule group meetings, discussion groups, and seminars. Aim 2: Fostering Sex and Gender Research: Core A will seek to stimulate further research with the following activities 2a) Gender Impact Studies Group discussion to consider the personal and societal impact of these problems unique to women, 2b) Support, maintain and expand the SCOf? Pelvic Floor Disorders Databank of over 12,000 images of over 600 research subjects from prior and ongoing projects 2c) convene an annual campus wide SCOR sponsored Pelvic Floor Research Day to foster interdisciplinary discussion 2d) Sponsor a National Workshop in Future Directions in Pelvic Floor Basic Science Research at the American Urogynecologic Society meeting. Aim 3 Biostatistics: Core A will manage data and work with project investigators to properly test study hypotheses. This will include overseeing data forms, data entry and management, biostatistical analysis and data quality control. Aim 4 Human Subjects: The core will assure Human Subject safety through active involvement with our IRB committee. This involvement will assure compliance with institutional and national regulations, tracking and assessing subject safety by monitoring adverse events, providing information to our outside subject safety committee as necessary. Core A will prepare regular reports from centralized logs concerning adverse events across all projects to increase detection of infrequent events that may occur in different projects.

3-D; 3-Dimensional; Admixture; Affect; Age; Apical; Area; Biomechanics; Body Tissues; Clinical; Computer Simulation; Computerized Models; Condition; Conflict; Conflict (Psychology); Connective Tissue; Control Groups; Data; Defect; Disease; Disorder; Distal; Distress; Dysfunction; Elements; Enterocele; Equipment and supply inventories; FLR; Failure (biologic function); Fascia; Female; Frequencies (time pattern); Frequency; Functional disorder; Genital System, Female, Vagina; H+ element; Hydrogen Ions; Hymen; Impairment; Individual; Inventory; Lead; Length; Levator Ani; Life Style; Lifestyle; Ligaments; Linear Models; Location; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Mathematical Model Simulation; Mathematical Models and Simulations; Measurement; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods and Techniques; Methods, Other; Modeling; Models, Computer; Models, Statistical; Morphology; Muscle; Muscle Cell Contraction; Muscle Contraction; Muscle Tissue; Muscle, Involuntary; Muscle, Smooth; Muscular Contraction; NICHD; NIDDK; NMR Imaging; NMR Tomography; National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Digestive Diseases and Kidney Disorders; Normal Range; Normal Values; Nuclear Magnetic Resonance Imaging; Numbers; Operation; Operative Procedures; Operative Surgical Procedures; Organ; Pattern; Pb element; Pelvic; Pelvic Floor; Pelvic Floor Disorders; Pelvic Region; Pelvic floor structure; Pelvis; Physiologic; Physiological; Physiopathology; Population Control; Position; Positioning Attribute; Probabilistic Models; Procidentia; Proctocele; Prolapse; Protons; Ptosis; Purpose; QOL; Quality of life; Race; Racial Group; Rate; Recruitment Activity; Rectocele; Recurrence; Recurrent; Relative; Relative (related person); Research; Role; Scanning; Severities; Shipping; Ships; Simulation, Computer based; Site; Smooth muscle (tissue); Social Support System; Statistical Models; Stocks, Racial; Structure of hymen; Structure of levator ani muscle; Support System; Surgical; Surgical Interventions; Surgical Procedure; Suspension substance; Suspensions; Symptoms; System; System, LOINC Axis 4; Techniques; Testing; Textiles; Tissues; Vagina; Vaginal; Vaginal Prolapses; Woman; Zeugmatography; case control; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; density; disease/disorder; expectation; fabric; failure; heavy metal Pb; heavy metal lead; hymen; in silico; insight; levator ani muscle structure; pathophysiology; recruit; response; size; social role; surgery; suspension; virtual simulation

Vaginal birth confers an 8-fold increase in the risk for a woman developing prolapse, a condition that results in 200,000 operations per year and carries up to a 25% reoperation rate at 10 years. Two primary causes for prolapse have emerged: 1) descent of the cervix and upper vagina (apical descent) involving the cardinal/uterosacral ligaments, and 2) neuromuscular damage to the levator ani muscles during vaginal birth. The relationship between these factors is unknown. It is the overall goal of our research to discover the basic mechanism whereby muscle and ligament failure interact producing prolapse. Our theoretical work suggests the working hypothesis that levator damage leads to opening of the levator urogenital hiatus and results in exposure of the vaginal wall to a pressure differential that pulls downward on the apical supports. Lack of data concerning ligament stiffness prevents a quantitative understanding of these relationships. We will recruit and test 50 asymptomatic volunteers and 50 women with pelvic organ prolapse to accomplish the following aims. Aim 1 will use a new servoactuator device to measure the in vivo ligament force-displacement behavior (stiffness) to determine the role of different ligament properties in prolapse. Aim 2 will make static and dynamic MRI images and clinical pelvic floor measurements to establish the relative contribution to apical descent by a) muscle impairment b) ligament properties. Aim 3 will create subject-specific 3D models of the cardinal and uterosacral ligaments, which will be used to and determine the measurement differences in cardinal and uterosacral elongation in apical descent. The results of this study will provide data that can lead to clinically relevant tests to, for example, identify which patients need an operation to support the apex. It will also provide the much needed data, validating an overall disease model concerning interactions between ligament support and muscle damage. This research will be helpful in developing strategies for improved prevention and treatment selection and a better understanding of why muscle damage at birth causes prolapse later in life.

Approximately 15% of women sustain pelvic muscle injuries during vaginal birth, demonstrable through magnetic resonance (MR) imaging. Our geometric model suggests the pelvic floor muscles stretch up to 3.3 times their original length during the second stage of birth. Based on MR imaging, histological, studies, and biomechanical modeling, when injury occurs, we hypothesize an initial rupture of the pubic attachment ofthe pubovisceral muscle (Type 1 injury), in some women followed by an avulsion of the pubic attachment of the arcus tendineus levator ani (Type 2 injury). We seek funds to characterize the variation of tissue in these injury zones and document their failure loads. AIM 1 will characterize the morphology and histology of pubovisceral and arcus tendineus tissues, bi-axial material properties where appropriate, and uniaxial failure properties in 30 cadavers. In 20 volunteers, we will use ultrasound elastography to characterize the effect of pregnancy on perineal body elasticity. AIM 2 will use Aim 1 data to refine a subject-specific, 3-D finite element viscohyperelastic biomechanical model of the second stage of labor from Station +2 on. We will test the above hypotheses with regard to the sequence of Type 1/Type 2 injuries, and run parametric studies to determine the biomechanical factors that increase or decrease the risk of Type 1 and Type 2 injuries. We will validate the model with stereophotogrammetric measurements of perineal descent in 10 laboring women. Since maternal exhaustion is a major risk for instrumented delivery and levator muscle injuries, in AIM 3 we will use a repeated measures design to quantify the outcomes in 40 healthy non-pregnant volunteers between 21 and 30 years of age to study the energetic cost of Valsalva pushing with and without (a) maximal arm and (b) arm and thigh muscle isometric contractions. These observations will yield insights into the factors associated with the greatest risk for injury, and should lead to better methods of preventing these injuries.

The Biostatistical and Biomechanical Measurements Core (BBMC) will provide biostatistics and biomechanical support to SCOR Projects I, II, and III. AIM1 is to assist with study design, power analyses and data analysis plans. AIM 2 is to provide engineering support for experimental, clinical and 3-D imaging measurements. AIM 3 is to provide support for database management and information exchange across SCOR Projects. AIM 4 is to conduct high quality statistical analyses across SCOR Projects, and AIM 5 is to provide mentoring and training of young investigators in these methods in conjunction with Core C. Core B will assist with technical aspects of tissue property and quantitative histology measurements in Project 1 (30 cadavers), as well as human subjects measurements (n=60) in Project 1. In Project 11 it will assist with post-natal quantification of pubovisceral muscles and their defects in MR images from up to 88 women. In Project 111 it will assist with measurements of vaginal support using biomechanical instrumentation, standardized 3-D MR images and clinical measurements in up to 100 women. Finally, Core B will continue to foster new academic collaborations and interface with industry partners, developing novel instrumentation and analytical techniques as needed.

We do not know why some women who give birth vaginally sustain an extensive major levator ani (LA) muscle tear. Nor do we know why 1 in 10 women suffer pelvic organ prolapse. In 2003, we began testing thishypothesis in a sample of women predisposed for LA injury because all had obstetric events associated with LA trauma (e.g. forceps, anal sphincter tear). With these high risk women, the tear was still only partial, less than 50% muscle fiber loss. Since it is major LA tear that is associated with prolapse when studied in multipara later in life, we need to learn about LA tear progression from first to second birth and how this contributes to prolapse later in life. We hypothesize that 1) exposure again to vaginal birth after an initial LA partial tear places a woman at high risk for more extensive LA tear, that 2) extension in LA tear is associated with increased pelvic organ descent, and this is because 3) the LA becomes unsupportive when it is no longer tethered to its origin. We aim to test these hypotheses in a highly efficient prospective cohort design. About 45% of our previously established cohort of first-birth women showed partial LA tear when evaluated by MRI. and the other half exhibited no evidence of tear despite also having obstetric risk factors for LA tear on first birth. We will study all of the women again to detennine if partial tear determines higher risk for extensive injury and increased prolapse when they birth again. All of the women in this established cohort have consented to further contact. We plan to evaluate those who have given birth vaginally a second time, comparing MRI data post first birth versus post second birth to quantify change in LA tear status, change in descent of the pelvic organs, and the relationship between the two. The degree of LA tear will be measured using the redesigned and novel instrumented speculum that eliminates crosstalk from intra-abdominal pressure during volitional contraction. Organ descent will be measured by comparing common organ position in both subject MRIs. This project has high impact through three independent pathways to clinical relevance. It will: 1) close the time-gap between the initial injury (first birth) and later life pronounced prolapse symptoms by demonstrating that injury extension and symptom progression are predicted by partial tear at first birth, 2) begin to shift the current paradigm of elective Cesarean for all to prevent LA injury to data-based selection criteria, and 3) pave the way for new interventions targeted to those women most at risk, those who give birth again after an initial partial LA tear on first birth.

Core A: Sex Differences Administrative Support Core will be responsible for the following five services to coordinate the three projects in this SCOR. Aim 1: Administration: Core A will provide administrative support to Projects 1,11, and 111 for recruitment. subject scheduling, forms generation, IRB issues, organization, and confidential filing. Centralized support will decrease cost and increase effectiveness. Aim 2: Human Subjects: Core A will assure ongoing safety of human subjects through active involvement with our IRB committee. This involvement will assure compliance with institutional and national regulations, track and assess subject safety by monitoring adverse events, and provide information to outside subject safety committee (DSMB) as necessary. This core will prepare regular reports from centralized logs from all Projects concerning adverse events to increase detection of infrequent events that require special attention. Aim 3: Fostering Sex and Gender Research: Core A will seek to stimulate further research with the following activities: a) convene an annual SCOR sponsored Pelvic Floor Research Day to foster interdisciplinary discussion across campus along with translational partners and mentees, and b) support, maintain, and expand the SCOR Pelvic Floor Disorders Data Bank of over 1,200 research subjects, totaling over 20,000 images from prior and ongoing projects. Aim 4: Budget: Core A will manage the fiscal responsibility of Project I, II, and III along with expenses of Cores A, B, and C. This will include assurance of appropriate distribution of funds to support all three projects throughout the entire length of the funding period. Aim 5: Presentation and Manuscript Production: Core A will be responsible for the administrative aspects of the dissemination of data and findings to research and clinical practitioners. Manuscripts and presentations will be submitted and tracked through Core A, allowing immediate translation of important sex-differences research to the community of researchers and physicians who can implement changes and improve prevention and treatment.

The Translation, Mentorship, and Team Science Service Core (TMTC) will prepare the next generation of interdisciplinary, translational team scientists through enhanced mentorship and expanded capacity in translation and dissemination of research results, providing a model for future investigators. We will leverage existing translational support, trainee development, and team science didactic opportunities that are in place at the University of Michigan (U-M). Specific resources include the U-M Clinical and Translational Science Award (CTSA) and The Michigan Institute for Clinical & Health Research (MICHR), as well as others. U-M SCOR scientists are seasoned team science practitioners, experiencing first-hand the invaluable insights emerging from multidisciplinary engagemenL Combining our team-science maturity and fertile inter-disciplinary environment with formal CTSA team science coursework will better train the next generation. AIM 1 will enhance widespread translation, dissemination, and public uptake of research findings. AIM 2 will provide supportive, effective mentorship for graduate, postgraduate, and early stage investigators. The TMTC will coordinate with Core B to assure trainee development includes the essential skills of design and analysis of data from research studies that include biomechanical and epidemiological measurements. AIM 3 will build interdisciplinary and team science skills in a cross-disciplinary cadre of trainees.

Abstract Approximately ?one in ten U.S. adults suffer from daily urinary incontinence; most of those affected are women? (NIDDK). Hence 12.6 million American women are afflicted by this distressing and socially stigmatizing problem, at a cost of $88.2 billion dollars annually. Despite the importance of this condition, cure rates in NIH- sponsored trials for stress and urge incontinence remain at 50% or lower. Why? The current conceptual framework on which treatments are based maintains that 1) stress incontinence is caused by poor urethral support, and 2) urge incontinence is caused by abnormal bladder contractility. Paradigm-shifting research by our group shows that the urethral sphincter complex, long overlooked as a causal factor, is responsible for 50% of stress incontinence and also plays a critical role in urge incontinence. Progress in understanding how the urethral closure mechanism works is currently hindered by two factors: 1) current testing strategies that are based on outmoded, simplistic, and artifact-prone 1960s technology, and 2) the lack of a detailed understanding of urethral structure-function relationships needed to guide research. AIM 1: Develop a state-of-the-art battery of urethral sensorimotor and vascular assessment tools: We will produce and validate novel measurement strategies using state-of-the-art sensor and advanced imaging strategies. These tools will include: a) an ultraflexible, microscale, multisite urethral pressure catheter; b) a physiologic urethral sensory testing apparatus; and c) a miniature wearable uroflowmeter and a daily activity monitor. AIM 2: Develop advanced ultrasound imaging equipment and strategies: The structure and function of the urethra is easily accessed by ultrasound, yet strategies and equipment to evaluate it are limited. In this Aim, we will develop: B-mode for dynamic anatomy, Doppler for vascular flow quantification, and elastography for urethral wall mechanical properties to measure real-time urethral kinematics that can be used by AIMS 1 & 3. AIM 3: Develop a multiscale 3D anatomical atlas and high-fidelity urethral multiphysics computer model for simulating how changes in individual structures and the effects of age and disease processes affect urethral function. We will a) produce the first in vitro 3D multiscale probability map and in vivo high-resolution MR scans of the female urethra. These data, along with emerging data from AIMS 1 & 2, will be used to b) create and validate the first finite element multiphysics urethral model that can be used by researchers to investigate how changes in individual urethral structural and functional parameters affect urethral closure pressure. The technical and conceptual tools provided by this work will stimulate research and launch hypothesis testing to clarify how the continence margin is determined and how age, diabetes, childbirth, race, genetics, and other factors affect urethral failure in women. This work will reveal currently unexplored therapeutic targets and bring science to the urethra's critical, but long overlooked, aspect of continence function.