Novel Approaches For Understanding Ciliary Assembly In Rare Childhood Diseases

Principal Investigator(s):

Susan Dutcher, Ph.D. - Genetics, Cell Biology and Physiology

Steven L. Brody, M.D. - Medicine

Status: Completed

Center(s): Center for Pediatric Pulmonary Disease

Award Mechanism: Interdisciplinary Research Initiative

Project Period: 2/1/2014 - 7/31/2016

Total Amount: $300,000

Collaborators: Amjad Horani, Thomas W. Ferkol, Philip Bayly, Mohamed Mahjoub

Project Summary:

With each breath, the human lung is exposed to inhaled bacteria, pollutants, and other airborne particulates. Cilia are specialized hair-like organelles that rely on hundreds of different proteins, including dynein motors, to sweep inhaled particulates from the lung in a coordinated fashion. Ciliary dysfunction is known or suspected in a number of genetic and acquired disorders known as ciliopathies, including primary ciliary dyskinesia (PCD), heart malformations, and other birth defects. The goal of this project is to discover new genetic mutations involved in cilia-related human disease by studying patients with known PCD, and model the genetic defects in algae and zebrafish to understand how various factors assemble dynein motors to allow them to function.

Aims:

•       Characterize binding partners of known PCD-related assembly proteins

•       Identify novel motor assembly genes identified in algae and test these gene candidates in zebrafish, human airway cells, and PCD subjects without identified disease-causing mutations

•       Using an alga, screen for suppressors of ciliary motor assembly as targets to rescue PCD mutations and test their function in model systems

Potential Impact: The proposed project will illuminate the causes of inherited (and possibly even acquired) ciliopathies, provide diagnostic tools, and potentially reveal new treatments for affected children