P01HD104436

Developmental Mechanisms of Human Meningomyelocele - Project Summary – Overall

The central goal of this program project application is to understand the mechanisms of meningomyelocele (MM), the most severe neural tube defect (NTD) compatible with survival. MM is a condition in which folic acid (FA) fortification has had a major impact on disease risk. This PPG aims to advance biomedical knowledge and make a high impact on our understanding of the molecular genetics of MM across the evolutionary scale. The purpose is to enhance our ability to determine disease risk and establish mechanisms by which FA alters risk.

MM is the most common birth defect of the central nervous system, affecting 3.7 per 10,000 live births. It is one of the high impact conditions prioritized by the NIH for research. In our preliminary data, we have achieved the following:

1. Constructed a cohort of over 1500 human trios with MM, stratified by whether the child was conceived in a FA-supplemented geography.
2. Established Xenopus laevis as a high-throughput model to assess human mutant alleles, gene-gene interactions, and FA exposure.
3. Established a number of murine NTD models with measured effects of FA on penetrance and expressivity.
4. Demonstrated a proven track record of applying these tools to study mechanisms of disease.

As a result of the extensive preliminary data, we have formulated this PPG with a two-fold thrust:

1. By taking advantage of the technical revolution in next-generation sequencing and CRISPR genetic engineering, we will uncover and functionally assess new MM risk factors.
2. By comparing phenotypes across the evolutionary timescale, we will enhance our understanding of the basic mechanisms of NTDS and the impact of FA.

The central theme running throughout the application is gene-environment interaction (GXE) due to the important role FA has on MM risk in human, mouse, and frog. This theme applies to all three projects and cores. Three cores will carry out essential functions and benefit each project:

1. Administrative Core: To facilitate communication and provide opportunities for scientific collaboration.
2. Epigenomics Sequencing Core: To provide essential functions in assessing FA-dependent DNA methylation and other impacts on chromatin and transcription.
3. Bioinformatics Core: To provide essential functions in data processing and harmonization, mutation identification, and custom computational solutions.

The specific aims of the PPG are:

1. To uncover a host of new developmental causes of MM from this unique human cohort, as well as from mouse and frog models.
2. To explore mechanisms by which FA reduces disease incidence in human, mouse, and frog.
3. To utilize mechanisms uncovered in mouse and frog NTD models to inform gene prioritization in human MM.

We believe that this PPG will have a major impact on our understanding of the cellular and molecular mechanisms underlying NTDS. It takes advantage of new breakthrough technology and will set the stage for improved diagnosis and ultimately prevention of disease.

San Diego University Of California

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]

La Jolla, California 92093 United States

Single Zip Code

Developmental Mechanisms of Human Structural Birth Defects (P01 Clinical Trial Not Allowed)) (RFA-HD-21-013)

Amendment Since initial award the total obligations have increased 392% from $1,417,141 to $6,965,574.