Ignite Creation Date:
2024-05-06 @ 7:51 PM
Last Modification Date:
2024-10-26 @ 3:15 PM
Study NCT ID:
NCT06167590
Status:
RECRUITING
Last Update Posted:
2023-12-12
First Post:
2023-05-22
Brief Title:
Integrins and Protocadherins in Glutamatergic Circuits Identification of Common Signaling Pathways and Molecular Targets in Anxiety and Major Depressive Disorders GAPsy
Sponsor:
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Organization:
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Study Overview
Official Title:
Integrins and Protocadherins in Glutamatergic Circuits Identification of Common Signaling Pathways and Molecular Targets in Anxiety and Major Depressive Disorders GAPsy
Status:
RECRUITING
Status Verified Date:
2023-05
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:
GAPsy
Brief Summary:
The aim of this study is to identify biologically viable targets for the treatment of major depressive disorder MDD and anxiety disorder AD with the ultimate goal of guiding physicians therapeutic strategies and identifying more effective and safer treatments for patients Following the inclusion and exclusion criteria the investigators will recruit 10 patients with a diagnosis of anxious-depressive disorder MDD-AD and 10 healthy controls HC subjects Each participant will be evaluated by a team of expert psychologists and physicians who will be conducting a structured interview and administering a set of psychopathological scales to assess the symptoms severity The participants will also undergo7T multimodal neuroimaging session including T1-weighted 1H-MRS and fMRI
In the second part of the study murine models will be used to study the role of integrin β3 Itgb3 and protocadherin 9 Pcdh9 in glutamatergic transmission at a molecular level and to evaluate whether the electrophysiological and behavioral defects identified in Itgb3- and Pcdh9-knockout mice can be restored by CRISPR-mediated transcription activation CRISPRa
In the second part of the study murine models will be used to study the role of integrin β3 Itgb3 and protocadherin 9 Pcdh9 in glutamatergic transmission at a molecular level and to evaluate whether the electrophysiological and behavioral defects identified in Itgb3- and Pcdh9-knockout mice can be restored by CRISPR-mediated transcription activation CRISPRa
Detailed Description:
The study is structured into two parts In the first part the investigators will be recruiting 10 patients with MDD-AD and 10 HC following the inclusion and exclusion criteria Each participant will be evaluated by a team of experienced psychologists and clinicians administering structured clinical interviews to assess the presenceabsence of axis I and II psychiatric disorders SCID-I and SCID-II first visit Furthermore in all subjects the degree of depressivemanic dysintomatology will be measured through the use of clinical scales and psychopathological tests such asthe Hamilton Depression Rating Scale HAM-D the Montgomery- Asberg Depression rating Scale MADRS the Hamilton Anxiety Rating Scale HAM-A and the Brief Psychiatric Rating Scale BPRSsecond visit within one week of the first screening visit Moreover additional clinical data will beextrapolated from medical records and interviews with psychiatrists if available
The investigators will also evaluate the suitability of each participant to undergo the multimodal acquisition of Magnetic Resonance Imaging MRI data with a 7T GE scanner The neuroimaging session performed during the third visit within one month of the second visit will include
T1-weighted image acquisition to study the volumetric differences of white and gray matter between subjects in the prefrontal-limbic pathway
fMRI to assess functional connections between prefrontal cortex and limbic system
1H-MRS to study glutamatergic neurotransmission within the anterior cingulate and dorsolateral prefrontal cortex
The sequences will be optimized thanks to the 32-channel brain coil NovaMedical to reduce artifacts and inhomogeneities in images
The second part of the study will involve murine models More specifically to assess whether Pcdh9 deficits affect the number and morphology of excitatory synapses electron microscopic analyses will be performed in Pcdh9-knockout mice Glutamatergic signaling will also be studied at the biochemical level the expression levels of all major glutamate receptor subunits ionotropic and metabotropic will be investigated by analyzing cortical protein lysates total lysates in adult mice 3-4 months In addition to identify finer changes in glutamate receptor expression their intracellular and surface expression will be analyzed using the BS3 crosslinking assay
The investigators will also proceed in the characterization of the interaction between integrin β3 and Protocadherin9 using co-immunoprecipitation analysis from mouse brain in case of positive results at least 3 replicates further analysis will be conducted to study whether the two proteins bind directly
Electrophysiological characterization of Itgb3 and Pcdh9 murine patterns in the medial prefrontal cortex at both synaptic and local network levels will also be performed and lastly an evaluation of functional recovery of behavioral and electrophysiological deficits mediated by CRISPRa will be conducted In this case experiments on murine models will be perform to determine whether overexpression of integrin β3 or protocadherin9 could compensate for defects in synaptic glutamatergic transmission caused by deficiencies in CAMs
The investigators will also evaluate the suitability of each participant to undergo the multimodal acquisition of Magnetic Resonance Imaging MRI data with a 7T GE scanner The neuroimaging session performed during the third visit within one month of the second visit will include
T1-weighted image acquisition to study the volumetric differences of white and gray matter between subjects in the prefrontal-limbic pathway
fMRI to assess functional connections between prefrontal cortex and limbic system
1H-MRS to study glutamatergic neurotransmission within the anterior cingulate and dorsolateral prefrontal cortex
The sequences will be optimized thanks to the 32-channel brain coil NovaMedical to reduce artifacts and inhomogeneities in images
The second part of the study will involve murine models More specifically to assess whether Pcdh9 deficits affect the number and morphology of excitatory synapses electron microscopic analyses will be performed in Pcdh9-knockout mice Glutamatergic signaling will also be studied at the biochemical level the expression levels of all major glutamate receptor subunits ionotropic and metabotropic will be investigated by analyzing cortical protein lysates total lysates in adult mice 3-4 months In addition to identify finer changes in glutamate receptor expression their intracellular and surface expression will be analyzed using the BS3 crosslinking assay
The investigators will also proceed in the characterization of the interaction between integrin β3 and Protocadherin9 using co-immunoprecipitation analysis from mouse brain in case of positive results at least 3 replicates further analysis will be conducted to study whether the two proteins bind directly
Electrophysiological characterization of Itgb3 and Pcdh9 murine patterns in the medial prefrontal cortex at both synaptic and local network levels will also be performed and lastly an evaluation of functional recovery of behavioral and electrophysiological deficits mediated by CRISPRa will be conducted In this case experiments on murine models will be perform to determine whether overexpression of integrin β3 or protocadherin9 could compensate for defects in synaptic glutamatergic transmission caused by deficiencies in CAMs
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