Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
| Status: | Recruiting |
|---|---|
| Conditions: | Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 10/14/2018 |
| Start Date: | January 2004 |
| End Date: | April 2021 |
Diagnostic and Clinical Characterization of Patients With Unusual Genetic Disorders of the Airways
The overall short-term goals of this project include the following: 1) identify the genes
that are key to the function of respiratory cilia to protect the normal lung; and 2) the
effects of genetic mutations that adversely affect ciliary function and cause primary ciliary
dyskinesia (PCD), which results in life-shortening lung disease. The long-term goal of this
project is to develop better understanding of the underlying genetic variability that
adversely modifies ciliary function, and predisposes to common airway diseases, such as
asthma and chronic obstructive pulmonary disease.
that are key to the function of respiratory cilia to protect the normal lung; and 2) the
effects of genetic mutations that adversely affect ciliary function and cause primary ciliary
dyskinesia (PCD), which results in life-shortening lung disease. The long-term goal of this
project is to develop better understanding of the underlying genetic variability that
adversely modifies ciliary function, and predisposes to common airway diseases, such as
asthma and chronic obstructive pulmonary disease.
A key component of lung defense is the efficiency of mucociliary clearance (MCC).
Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This ongoing
project is designed to identify additional disease-causing mutations in PCD, and correlate
the molecular etiologies with the ciliary phenotype (ultrastructure, wave form and beat
frequency). We have recently shown that the normal human cilium has a distinctive waveform,
i.e. beats in-plane with defined curvatures and amplitudes for the effective (forward) and
recovery stroke. We hypothesize that discrete sets of genes contribute to the structure and
function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and central pair (CP)
and radial spoke (RS) complex (CP/RS), and that we can identify novel genetic mutations in
different structural components of the cilium that will have different effects on ciliary
ultrastructure, wave form, and beat frequency. Importantly, we are now able to identify
patients with PCD who do not have hallmark diagnostic ultrastructural defects, based on
distinctive clinical phenotypes (including situs inversus), low or borderline nasal NO
production, and abnormal ciliary motility. Identification of PCD patients with normal ciliary
ultrastructure (~16% of PCD patients at UNC) offers the opportunity to discover mutations in
genes that cause functional, but not ultrastructural, defects (such as DNAH11), and to
correlate those mutations with ciliary waveform abnormalities. Over the past 4 years, we have
made great progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of
ODA defects in PCD, and ~35% of PCD overall. We will extend our search for disease causing
mutations in PCD, using several different approaches, including studies of additional
candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and
family-based studies. Taken together, these studies will provide new insights regarding the
relationship of mutations in specific genes to ciliary ultrastructural and functional
defects. These studies will not only greatly enhance our ability to diagnose PCD, but will
also lead to discovery of "milder" genetic mutations associated with normal ciliary
ultrastructure, and likely some residual ciliary function. Ultimately, this will allow future
studies of the role of partial loss of ciliary function in the predisposition to more common
airways diseases, such as chronic bronchitis and chronic obstructive pulmonary disease.
Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This ongoing
project is designed to identify additional disease-causing mutations in PCD, and correlate
the molecular etiologies with the ciliary phenotype (ultrastructure, wave form and beat
frequency). We have recently shown that the normal human cilium has a distinctive waveform,
i.e. beats in-plane with defined curvatures and amplitudes for the effective (forward) and
recovery stroke. We hypothesize that discrete sets of genes contribute to the structure and
function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and central pair (CP)
and radial spoke (RS) complex (CP/RS), and that we can identify novel genetic mutations in
different structural components of the cilium that will have different effects on ciliary
ultrastructure, wave form, and beat frequency. Importantly, we are now able to identify
patients with PCD who do not have hallmark diagnostic ultrastructural defects, based on
distinctive clinical phenotypes (including situs inversus), low or borderline nasal NO
production, and abnormal ciliary motility. Identification of PCD patients with normal ciliary
ultrastructure (~16% of PCD patients at UNC) offers the opportunity to discover mutations in
genes that cause functional, but not ultrastructural, defects (such as DNAH11), and to
correlate those mutations with ciliary waveform abnormalities. Over the past 4 years, we have
made great progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of
ODA defects in PCD, and ~35% of PCD overall. We will extend our search for disease causing
mutations in PCD, using several different approaches, including studies of additional
candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and
family-based studies. Taken together, these studies will provide new insights regarding the
relationship of mutations in specific genes to ciliary ultrastructural and functional
defects. These studies will not only greatly enhance our ability to diagnose PCD, but will
also lead to discovery of "milder" genetic mutations associated with normal ciliary
ultrastructure, and likely some residual ciliary function. Ultimately, this will allow future
studies of the role of partial loss of ciliary function in the predisposition to more common
airways diseases, such as chronic bronchitis and chronic obstructive pulmonary disease.
Inclusion Criteria:
- Patients who have a high suspicion for the diagnosis of PCD, based on clinical
features
Healthy Volunteers who have a family member with confirmed PCD.
We found this trial at
1
site
Chapel Hill, North Carolina 27599
(919) 962-2211
Phone: 919-966-6780
University of North Carolina at Chapel Hill Carolina’s vibrant people and programs attest to the...
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