CA24124 - Network for the Advancement of Neutropenia Research and Patient Support (Neutro-NARPS)

+302810394637
coordinator@neutro-narps.eu

 

LEADER

Dr Francesca FIOREDDA
francescafioredda@gaslini.org

 

Co-LEADERS

Prof Aristides ELIOPOULOS
eliopag@med.uoa.gr
 
Dr Grigorios TSAKNAKIS
g.tsaknakis@uoc.gr
 

How can I participate?

Read the Action Description MoU
Inform the Main Proposer/Chair of your interest (e.papadaki@uoc.gr)

Apply to join your Working Groups of interest

Please note, Management Committee nominations are carried out through the COST National Coordinators

Working Group 2
ACQUIRED AND LIKELY-ACQUIRED CNP AND INFLAMMATION

The  main  objective of  WG-2  is  to  investigate the  interplay between inflammation, nutrition and microbiome and their association with the pathophysiology of acquired idiopathic and likely-acquired CNP and with the occurrence of CH, CVD, cancer and AID within this group of patients. WG-2 is expected to shed light and provide new insights into the underlying pathogenetic mechanisms and drive the development of novel and tailored therapeutics for CNP patients.

Task 1: Investigation of the congenital basis of acquired/likely-acquired CNP.

This task will test the hypothesis that a constitutional/congenital background might exist in likely-acquired and idiopathic CNP and that neutropenia is an epiphenomenon of immune dysregulation. WES analysis will be performed in children, adolescences and adults with late onset/long-lasting CNP and idiopathic CNP (a) to identify/validate variants with high probability to display a causative role in the pathogenesis of CNP and (b) to identify cases with common genetic background indicating a potential continuum in the spectrum of CNP from the childhood to adulthood.

Task 2: Investigation of the inflammation link between acquired/likely-acquired CNP and CH.

NGS results from patients with likely-acquired and idiopathic CNPs will provide the basis for association analyses between inflammatory pathways, CNP phenotypes and CH. Clinical-laboratory markers of inflammation, pro-inflammatory cytokines profile, NETosis-related pro-inflammatory markers in plasma, and immunophenotype of CNP patients will provide novel insights into associations between inflammatory burden, CH, MDS/AL progression. These analyses will also identify molecular pathways that can be targeted for therapeutic intervention.

Task 3: Investigation of the inflammation link between acquired/likely acquired CNP, cancer, CVD and AID.

Parameters related to chronic inflammation described in Task 2 will be investigated for their association with the development of cancers, CVD, AID in patients with likely-acquired and idiopathic CNP. The medical history and specific questionnaires will be used at diagnosis and during follow-up. Autoantibody profiling and cancer screening tests will be evaluated and monitored. WES data from Task 1 will be analysed for AID identification. Quantitative/qualitative activity of the heart will be recorded using electro/echocardiograms. Quantification of carotid arterial plaque by ultrasound for identification of atherosclerosis and evaluation of CVD risk will be also used. Routine PB biochemical parameters and specific biomarkers (such as troponins, natriuretic peptides and hsCRP) will be evaluated and associated with the inflammatory markers in CNP patients.

Task 4: Investigation of the inflammation link with nutrition in acquired/likely acquired CNP.

Explore the relationship between dietary patterns, inflammatory responses, and CNP development. Using UK Biobank data, this task will investigate associations between adipokine levels and ANCs to determine how variations in caloric intake and adipokine profiles may influence neutrophil homeostasis. These analyses will use of a systemic immune-inflammation index, SII, calculated from routine complete blood count. Tailored dietary questionnaires for CNP patients will be developed and distributed across participating Institutions to validate and expand upon the findings from the UK Biobank, to uncover how dietary patterns impact CNP. Longitudinal monitoring of adipokines and inflammatory markers will be conducted to assess progression to MDS/AL, CVD, AID, cancers. GWAS data will be used to identify genetic variants linked to CNP under particular nutritional states, with a focus on genes regulating metabolic processes identified through analysis of the single-cell atlas.

Task 5: Investigation of the link with microbiome in acquired/likely-acquired CNP.

The microbiome has recently surfaced as a crucial regulator in human health [42,43]. This task will test the hypothesis that the microbiome may influence the immune function and inflammation in the context of CNP. Metagenomic profiling of circulating cfmDNA will be performed in serum from patients with likely- acquired and idiopathic CNP to identify possible alterations compared to healthy individuals at diagnosis and longitudinally. Additional NGS profiling of different body sites (gut, oral) will allow the identification of possible sources for the microbial infiltration in the context of CNP. Quantification of cfmDNA with artificial DNA spikes will allow additional stratification of patients and understanding of the dynamics affecting it. Correlation analyses will elucidate the relations between cfmDNA, microbiome composition at different body sites and clinical parameters, inflammatory status and outcome of CNP patients.

Milestones:

M2.1. WG Meetings (1st quarter of each year) which will be based on the progress made in WG-2 followed by the respective reports (months 12, 24, 36, 48).

M2.2. Calls for STSMs (2nd and 4th quarter of each year) for training of young scientists on the technologies developed in WG-2 followed by the relative technical and scientific reports (months 12, 24, 36, 48).