R01HD111399

Mechanisms of ciliopathy associated structural birth defects - Project summary/abstract

Cilia are complex structures with more than 1,300 proteins involved in their formation and function.

During development, disruption of cilia function causes gestational lethality and mild to severe birth defects.

Variants in cilia proteins are causally associated with more than 35 ciliopathy syndromes.

Ciliopathy patients have a wide range of phenotypes affecting nearly every organ system.

Despite the cilium's clinical importance, the functions of the cilium and molecular pathways the cilium regulates are poorly defined.

To understand the pathophysiological mechanisms driving ciliopathy birth defects, we are extending and utilizing protocols, expertise, and tools developed within the UAB U54 Center for Precision Animal Modeling (CPAM).

We will identify and characterize variants of interest derived from patient and variant repositories from local, regional, and national/international sources.

Both variants of unknown significance (VUS) in known ciliopathy genes and predicted deleterious variants of interest identified in novel candidate ciliopathy genes that we prioritize through this application will be selected.

Each variant will undergo robust assessment based on known or predicted deleteriousness, pathway and protein interactions, and phenotype and functional associations as compared to known ciliopathies.

Prioritized variants will be subjected to a robust wet lab process to test pathogenicity, determine ciliopathy protein cellular localization, and screen rapidly for cilia related phenotypes in zebrafish F0 crispant mutants.

For variants that remain highly prioritized after these steps, we will generate precision engineered mouse models corresponding to the patient variant.

These models will undergo phenotype analyses to assess the clinical correlation between the model and the patient.

We will analyze the variant's impact on cilia assembly, morphology, formation of specialized cilia sub-compartments, and disruption of cilia protein interaction networks.

We will determine the impact of the variant on developmental signaling pathways known to be associated with the cilium as well as identify novel pathways not previously identified as being regulated by the cilium.

To accomplish the goals of the project, we have assembled a team with a wide range of expertise in medicine, genetics and molecular diagnostics, computational biology, bioinformatics, and data science, biochemistry, cell biology, and animal model generation and phenotyping.

Collectively we will confirm the functional impact of variants identified in patients with ciliopathy-like birth defects and patients with variants in genes predicted but not already well known to affect the cilium or its activity.

The outcomes from this project will uncover novel cilia protein interactions and subcomplexes involved in cilia formation and maintenance, cilia protein transport, and cilia sensory and signaling activities.

This work will also support definitive diagnoses for patients with cilia associated birth defects and generate data that can be used to predict potential therapeutic strategies.

We will also develop and disseminate patient relevant models and bioinformatics tools for the broader community.

University Of Alabama At Birmingham

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]

Birmingham, Alabama 352940004 United States

Single Zip Code

Screening and Functional Validation of Human Birth Defects Genomic Variants (R01 Clinical Trial Not Allowed) (PAR-21-229)

Amendment Since initial award the total obligations have increased 100% from $602,956 to $1,205,912.