R01HD105714

Rest/NRSF, miRNAs, and Tissue Remodeling in Adenomyosis Pathophysiology - Project Summary

Adenomyosis is a nonmalignant uterine disease characterized by endometrial stroma and glands found within the myometrium. Adenomyosis has been associated with heavy and painful menstrual periods, pelvic pain, pain with intercourse, and reproductive dysfunction. However, now that imaging is identifying adenomyosis in younger and more varied women than those electing hysterectomy where pathological diagnosis occurred, many of our assumptions about the clinical disease are changing.

Additionally, the only widely accepted and effective treatments for adenomyosis, hysterectomy and hormonal suppression, are unacceptable for this wider group of women. Much of our uncertainty on diagnosis and treatment for adenomyosis stem from our uncertainty on its pathogenesis. The most common theory of adenomyosis development centers on the involvement of tissue injury and repair mechanisms with resulting adenomyosis development from invagination of the endometrial basalis into the myometrium (the invasion/invagination theory).

While emerging data support a role for this theory and the involvement of cell migration, proliferation, and invasion in adenomyosis development, a detailed understanding of the mediators and mechanisms is clearly lacking. To fill this critical gap in our knowledge, we will perform a series of experiments which integrate well-defined human specimens, novel mouse models, and rigorous in vitro approaches to identify key components of a REST-miRNA-tissue remodeling cascade and demonstrate the functionality of this pathway in the pathogenesis of adenomyosis.

The specific hypothesis to be tested in this application is that reduced expression of endometrial and/or myometrial REST induces alterations in a miRNA-mediated tissue remodeling cascade which augments adenomyosis development. To test this hypothesis, we will delineate the expression of a novel REST-miRNA mediated tissue remodeling pathway in adenomyosis and define REST's function using novel experimental mouse models.

Using in vitro models for cell proliferation, migration, and invasion, we will decipher cell-to-cell communication between myometrial-endometrial REST-miRNA tissue remodeling pathway signaling relevant to adenomyosis pathophysiology. Together, these experiments will provide novel insight into the role of REST in adenomyosis development and, in turn, may lead to the identification of novel treatment targets for this disease.

University Of Kansas Medical Center Research Institute

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Kansas City, Kansas 66160 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 387% from $642,705 to $3,129,764.