Ignite Creation Date:
2024-05-06 @ 6:00 PM
Last Modification Date:
2024-10-26 @ 2:40 PM
Study NCT ID:
NCT05514470
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-28
First Post:
2022-06-17
Brief Title:
Impact of Mutations in Aminoacyl TRNA Synthetases on Protein Translation and Cellular Stress
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Impact of Loss-of-function Mutations of Genes Encoding Cytosolic Aminoacyl-tRNA Synthetases on Protein Translation and Responses to Cellular Stress
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FIBROMARS
Brief Summary:
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease liver damage neurological and digestive disorders and systemic inflammation These are rare and severe diseases whose pathophysiology is poorly understood
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation
Detailed Description:
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease liver damage neurological and digestive disorders and systemic inflammation These are rare and severe diseases whose pathophysiology is poorly understood
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation
The parameters below will be studied in vitro in cell culture from skin biopsies of patients and control cells
Determination of total protein content
The incorporation of d-methionine leucine tyrosine or phenylalanine into proteins
The study of polysomes profiling
The study of the assembly of the ribosomal 43S pre-initiation complex
The phosphorylation of eIF2α and 4EBP and the expression of ATF4
Ribosome profiling
Transfer RNA tRNA sequencing
The production of reactive oxygen species ROS
The results of these studies will be compared
Between patient cells and control cells
Between genetically corrected patient cells by stable transfection of the wild-type cDNA of the concerned genes and uncorrected cells
Between patient cells cultured in medium enriched with the corresponding amino acid
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation
The parameters below will be studied in vitro in cell culture from skin biopsies of patients and control cells
Determination of total protein content
The incorporation of d-methionine leucine tyrosine or phenylalanine into proteins
The study of polysomes profiling
The study of the assembly of the ribosomal 43S pre-initiation complex
The phosphorylation of eIF2α and 4EBP and the expression of ATF4
Ribosome profiling
Transfer RNA tRNA sequencing
The production of reactive oxygen species ROS
The results of these studies will be compared
Between patient cells and control cells
Between genetically corrected patient cells by stable transfection of the wild-type cDNA of the concerned genes and uncorrected cells
Between patient cells cultured in medium enriched with the corresponding amino acid
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2022-A00061-42 | OTHER | ID-RCB number | None |