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Project J3-2532

Bradykinin-mediated angioedema: Novel biomarkers and genetic predisposition

Research project ARRS.
Code: J3-2532
Period 1.9.2020 - 31.8.2023
Head: Assist Prof Matija Rijavec, BSc (Microbiol), PhD
ARRS classification: Medicine/Human reproduction
Annual: 0,23 FTE in 2020

Organisations:  University Clinic of Respiratory and Allergic Diseases    Golnik; University of Ljubljana, Faculty of Chemistry and Chemical Technology; University of Ljubljana, Faculty of Medicine

Researchers.


Description of the project

Angioedema (AE) is self-limiting and localized oedema of the subcutaneous and submucosal tissue, due to transiently increased vascular permeability in the deeper layers of the dermis and in the subcutaneous tissue. Clinically it is characterized by swelling of the face, lips, tongue, larynx, abdomen, genitalia or extremities. AE often occurs as part of urticaria, however, when recurrent angioedema develops without urticaria, the patient should be diagnosed as having isolated/primary AE. It is estimated that the prevalence of having at least one isolated angioedema attack during the entire lifetime is up to 10%.

Around 70% of AE is mediated by mast-cell mediators, the key being histamine, the so called histamine-mediated AE (H‑AE). The treatment of choice are antihistamines and corticosteroids. The rough remainder (30%) is caused by dysregulation of the bradykinin (Bk)-pathway, the so called Bk-AE, which represents the main focus point of the current project. Bk is a potent vasodilator and increases vascular permeability. Dysregulation of Bk metabolism results in different types of acquired and hereditary recurrent primary AE not responsive to antihistamines and corticosteroids. The treatment requires interventions that targets Bk pathways.

Patients with AE are often misdiagnosed; the rate of misdiagnosis can be up to around 50% with the biggest diagnostic hurdle lying in discrimination between allergic (H-AE) and non-allergic (Bk-AE). This translates to delays in diagnosis which are long and common. However, if AE patients are untreated or not treated correctly, the attacks can be frequent, tremendously effecting the quality of life. Patients can be debilitated by symptoms for several weeks a year, what is also associated with huge economical burden. Furthermore, laryngeal oedema as the most worrisome presentation of AE if treated wrongly can cause death by asphyxiation. Since, different AE types, underlined by different causes, require different treatment regimens, the establishment of the correct diagnosis is therefore of utmost importance. As evidenced above, distinguishing Bk-AE from H-AE remains the most significant and frequent dilemma faced by the clinician during an evaluation of a patient with AE, further adding to the problem is a lack of any available diagnostic test to discriminate between the two types. The diagnosis is therefore often established by excluding alternative diagnoses, which is as previously mentioned associated with misdiagnosis and delay in diagnosis.

The project itself will be composed of several inter-linked activities, divided into different, conceptually similar parts (work packages, WPs). It will range from recruitment of patients with comprehensive clinical evaluation, followed by an attempt to discover and validate clinically useful biochemical biomarkers to discriminate between Bk-AE and H-AE (WP1 and WP2). This will help us to identify patients who will benefit from Bk pathways targeting therapy. A large part of the project will be directed towards the identification of genetic causes/predisposition (WP3 and WP4) and disease-modifier genes (WP5) to Bk-AE employing different complementary strategies and methods, and basic functional characterization (WP6) of newly identified variants (in known HAE-related and newly discovered genes). The final goal of the project is the identification of the biomarkers and genetic predisposition (factors), including both genetic causes and disease-modifiers, for Bk-AE. This will in turn allow us to better understand the underlying mechanism and manage patients with AE.

Project timeline

 

Year 1

Year 2

Year 3

 

1

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3

4

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12

1

2

3

4

5

6

7

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12

1

2

3

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12

WP1

T1.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T1.2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

WP2

T2.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T2.2

 

 

 

 

 

 

 

 

 

 

T2.2

 

 

 

 

 

 

 

 

 

 

 

 

WP3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T3.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T3.2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

WP4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T4.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T4.2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T4.3

 

 

 

 

 

WP5

T5.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T5.2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T5.3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T5.4

 

 

 

 

 

WP6

 

 

 

 

 

 

 

 

 

 

T6.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T6.2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T6.2

 

 

 

 

 

 


Project work packages and their realization

Work package (WP)

Tasks (T)

Milestones & Deliverables

Work Distribution

WP1

Identification of clinically useful biomarkers

T1.1

Collect samples and clinical data from patients with Bk-AE & H-AE

Samples of approx. 100 patients, clinical & laboratory data

Clinic Golnik

T1.2

Measurement of stimulated kallikrein activity and cHMWK

Evaluation of diagnostic validity of biochemical markers

Faculty of Chemistry and Chemical Technology, UL

Clinic Golnik

WP2

Validation of biochemical biomarker(s)

T2.1

Collect samples & clinical data

Samples of approx. 300 patients, clinical and laboratory data

Clinic Golnik

T2.2

Measurement of biomarkers

Diagnostic value of biochemical biomarkers

Faculty of Chemistry and Chemical Technology, UL,

Clinic Golnik

WP3

Identification of genetic factors in known HAE-related genes

T3.1

WES in Bk-AE

WES in selected patients with Bk-AE

(from WP1 & WP2)

Clinic Golnik

T3.2

Analysis of WES for known HAE genes

Results of WES

Identification of disease-causing variants in known HAE-related genes

(SERPING1, F12, PLG, ANGPT1, KNG1)

Clinic Golnik

WP4

Discovery of novel genetic factors causing HAE

T4.1

Patient selection and recruitment

DNA samples, clinical and laboratory data, selected families

Clinic Golnik

T4.2

WES in U-HAE

Results of WES

Discovery of novel genetic factors causing U-HAE

Clinic Golnik

T4.3

Reanalysis of WES (from WP3)

Results of reanalysis

Identification of same causal genes responsible for HAE in other Bk-AE patients

Clinic Golnik

WP5

Identification of disease-modifier genes

T5.1

Patient selection

Selected DNA samples of C1-INH-HAE patients (variable disease severity and asymptomatic) from biobank

Clinic Golnik

T5.2

WES in selected C1-INH-HAE patients

Results of WES

Identification of genetic variants/genes influencing disease severity and penetrance in C1-INH-HAE

Clinic Golnik

T5.3

Genotyping of selected variants in all C1-INH-HAE patients

Confirming the relevance of genetic variants/genes influencing disease severity and penetrance in C1-INH-HAE (> 150 patients)

Clinic Golnik

T5.4

Reanalysis of WES data from WP3

Confirming the relevance of genetic variants influencing disease severity in

Bk-AE

Clinic Golnik

WP6

Biological and functional relevance

T6.1

Bioinformatics

In silico predicted functionality of the identified variants/genes

Medical Faculty, UL,

Clinic Golnik

T6.2

Functional analysis

Functional analysis of variants with best predicted potential

Medical Faculty, UL,

Clinic Golnik