Textová podoba smlouvy Smlouva č. 27259951: DODATEK O HOSTOVÁNÍ KE SMLOUVĚ O ÚČASTI NA PROGRAMU MERIT

                        DODATEK O HOSTOVÁNÍ KE SMLOUVĚ O ÚČASTI NA PROGRAMU MERIT

	

mezi

Středočeské inovační centrum, spolek
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Národní ústav duševního zdraví


Tento DODATEK O HOSTOVÁNÍ KE SMLOUVĚ O ÚČASTI NA PROGRAMU MERIT
uzavřené dne 11. dubna 2023 (dále jen „Dodatek o hostování“) uzavřely následující smluvní strany:


(1) Středočeské inovační centrum, spolek se sídlem Zborovská 81/11,150 00 Praha 5 IČO: 042 28 235
zastoupený Mgr. Pavlem Jovanovičem, statutárním ředitelem

(dále jen „Koordinátor“)
(2) Národní ústav duševního zdraví
se sídlem Topolová 748, 250 67 Klecany
IČO: 00023753
Zastoupená PhDr. Petrem Winklerem, Ph.D., ředitelem č.ú. 25234081/0710 vedený u Česká národní banka

(dále jen „Partner“)

(Koordinátor a Partner společně jako „Strany“)

PREAMBULE
(A) Strany uzavřely Smlouvu o účasti na programu MERIT (dále jen „Smlouva“), na jejímž základě je realizována jejich spolupráce při realizaci Programu a upraveny podmínky vzniku práva na poskytnutí Podpory.
(B) Realizace Projektu postoupila do další fáze, pročež Koordinátor vyzval Partnera k uzavření tohoto Dodatku o hostování.
(C) Partner v postavení Implementující organizace má zájem nabýt účinností tohoto Dodatku o hostování postavení Hostující organizace, se všemi právy a povinnostmi příslušejícími k tomuto postavení.

Strany v souladu s článkem 9 Smlouvy přistupují k uzavření Dodatku o hostování o následujícím znění:

1. Definice a výkladová pravidla
1.1. Není-li v tomto Dodatku o hostování uvedeno jinak, uplatní se v plném rozsahu definice a výkladová pravidla převzatá Stranami v článku 1 Smlouvy.

2. Předmět a prohlášení stran
2.1. Strany prohlašují, že
2.1.1. Výzkumník předložil Projekt, jehož specifikace tvoří přílohu č. 1 Dodatku o hostování;
2.1.2. Projekt předložený Výzkumníkem splňuje požadavky Programu;
2.1.3. Výzkumník má zájem realizovat Projekt u Partnera;
2.1.4. Výzkumník byl vybrán v rámci výběrového procesu Programu a jeho výběr, včetně přiřazení k Partnerovi, byl oficiálně schválen Řídicím výborem (Steering Committee) – Protokol o výběru Výzkumníka a jeho přiřazení k Partnerovi tvoří přílohu č. 2 Dodatku o hostování.

2.2. Partner se zavazuje nejpozději do 1. října 2024, od uzavření Dodatku o hostování uzavřít s vybraným výzkumníkem VYMAZÁNO, Pracovní smlouvu svým obsahem odpovídající Pokynům k Pracovní smlouvě (viz Příloha č. 3 Smlouvy). Nebude-li Pracovní smlouva dle předchozí věty v daném termínu uzavřena, pozbývá tento Dodatek o hostování účinnosti a Partner ztrácí postavení Hostující organizace.
2.3. Partner se dále zavazuje poskytnout Vybranému výzkumníku Spolufinancování za podmínek a v rozsahu stanoveném Smlouvou.
2.4. Partner bere na vědomí, že účinností tohoto Dodatku o hostování nabývá postavení Hostující organizace s právy a povinnostmi příslušejícími tomuto postavení. Tím nejsou dotčena další práva a povinnosti plynoucí Partnerovi ze Smlouvy.

3. Ostatní a závěrečná ustanovení
3.1. Tento Dodatek o hostování nabývá účinnosti dnem jeho zveřejnění v registru smluv.
3.2. Ve zbytku zůstávají ustanovení Smlouvy nedotčena.

	V 	dne  	


	VYMAZÁNO

	         Koordinátor
Mgr. Pavel Jovanovič, statutární ředitel
	
	Partner
PhDr. Petr Winkler, Ph.D., ředitel


Příloha č. 1 – Specifikace Projektu
Příloha č. 2 - Protokol o výběru Výzkumníka a jeho přiřazení k Partnerovi (Zápis z jednání Steering Committee)
Obě přílohy jsou součástí Dodatku.


1. EXCELLENCE

ACRONYM: TRS

1.1 Quality and pertinence of the project’s research and innovation objectives
What is schizophrenia?
Schizophrenia is a severe mental disorder that affects how a person thinks, feels, and behaves. It is classified as a psychotic disorder, which reflects the involvement of disconnection from reality. Schizophrenia mostly starts at 15-25 years of age in men and 25-35 in women. It is a chronic, life-long condition. Schizophrenia affects about 0.5-1% of people worldwide (1). Besides the derailment of the lives of these patients, a significant collateral impact is elicited on people around.
What is the current state-of-the-art in treating schizophrenia?
The first pharmacological medications for psychotic patients appeared 75 years ago. The principle of treatment exploited the inhibition of dopaminergic signaling. While the medications were groundbreaking and many improvements have been developed since then, a significant problem persists: about 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics (2). They are said to have treatment-resistant schizophrenia (TRS).
Benefits and problems with clozapine treatment
The only medication that remains effective for TRS is clozapine. Early identification of TRS may allow for the timely introduction of clozapine, the only medication with worldwide regulatory approval for managing TRS (3), which is effective in 75% of all TRS cases on the condition the treatment is initiated at a very early disease stage (4). However, physicians hesitate and delay the prescription of this medication due to its severe side effects, e.g. agranulocytosis. As a result, each year of delay in clozapine initiation in TRS is associated with a 15% decrease in the chance of functional improvement, reduced treatment effectiveness, increased number of hospital admissions, and more frequent use of concurrent electroconvulsive therapy (5). Physicians do not have tools to assess the benefit-risk ratio while they are or are not describing clozapine (6).
How can we predict which patients can benefit from clozapine early after the onset of psychosis?
As stated in the recent review, diagnostic biomarkers for TRS were explored through correlations with single nucleotide polymorphism in neurotransmitter genes, including genes for dopamine, serotonin, and glutamate, alterations of signaling molecule Akt 1, or several inflammatory factors, such as chemokines or interleukin-6. However, the information remains fragmentary, and a more comprehensive picture is needed (7).
What is needed?
The identification of diagnostic markers of TRS will likely be achieved through multimodal analyses of patients with schizophrenia, mainly if they include brain imaging, are longitudinal, and the dataset contains not only comprehensive hospital laboratory tests but also experimental analyses and biochemical assessments through -omics.

Moving beyond the-state-of the-art
The Institute of Mental Health in Czechia currently has the world´s largest longitudinal, densely phenotyped database and biobank of first-episode schizophrenia-spectrum patients. The collection is called “Early-Schizophrenia Outcome”, ESO). ESO includes the most extensive samples ever applied to the multimodal, longitudinal survey in the early schizophrenia stage, encompassing MRI neuroimaging to detailed laboratory workup. The longitudinal design allows us to integrate crucial information on treatment response and thus a priori distinguish a group of TRS and non-TRS individuals. The “ESO” collection is an exquisite tool for assessing differences in the pathophysiology of patients responding to antipsychotics versus TRS patients, and led to the discovery of new diagnostic markers for TRS.
Hypothesis

We hypothesize that application of plasma of patients responding to antipsychotic medications versus patients with TRS will elicit different profiles in sensor cells in cell culture. Also,, the blood cells of responsive patients versus those with TRS will respond to antipsychotic exposure, leading to different transcriptomic signatures. The factors in which these two groups differ may include messenger RNA QPCR profile and intracellular and membrane proteins. These molecules can be readily detected in a hospital lab and could form a diagnostic panel for TRS. These markers could be monitored longitudinally, and in studies where brain imaging and other factors are investigated, new guidelines could be established that enable the facilitation of the prescription of efficacious medication, e.g., clozapine.

Specific objectives

We propose using blood samples of patients from the ESO collection and employing an experimental approach and -omics analyses in determining the differences between patients who respond to anti- psychotic therapies versus TRS patients.
1. We will apply plasma from the responsive and resistant patients and healthy controls to sensor cells, including peripheral blood mononuclear cells (PBMC), primary neuronal cells, glia, and astrocytes. The output of these essays will be data from new-generation RNA sequencing (NGS) of the sensor cells. In that way, we will learn whether plasma carries soluble factors that differ in the groups of our interest;
2. Collect PBMC of responsive and TRC patients, healthy controls, and incubate them with therapeutic doses of anti-psychotic medications used in their treatment (each subject’s cells in different wells can be exposed individually to multiple medications). PBMC will then be harvested, and their transcriptome investigated. Initially, we will employ NGS and later will transfer to cost-effective QPCR. These changes will provide us with information about differences in the impact of medications between responsive and resistant individuals.
3. Assess data from Objectives 1 and 2, and employ them in designing and testing PBMCs to establish a diagnostic panel by employing QPCR for monitoring selected gene expression and/or FACS analysis for intracellular or cell surface markers.

4. Relate the rich data from these analyses to other data within the ESO database and brain imaging patterns.
Significance of the objectives
Our objectives focus on uncovering diagnostic markers for patients with TRS that may include soluble factors, expression of messenger RNA, and cell surface markers in the blood, which is a readily obtainable specimen and feasible to use in a clinical setting. The existence of such markers would help resolve a significant management problem affecting 30% of patients with schizophrenia. This tool would help a physician give patients TRS clozapine and reduce delays while trying other treatments. The delays put patients at risk of developing histopathological changes and irreversible degeneration of their brain tissue.
Measurability and verifiability of outcomes of objectives
All proposed experiments involve objective assays that will result in quantifiable data. The outcome will be five peer-reviewed publications in journals at the 1st-2nd quartile.
Achievability of the objectives
Plasma samples from healthy control subjects and patients responsive to antipsychotics versus suffering TRS are available from the large ESO biobank. Laboratory for cell cultures and molecular approaches are available at the NIMH, except for the fluorescein-activated cell sorter (FACS) instrument. BD FACS Aria Cell Sorter is available in the Institute of Organic Chemistry and Biochemistry, where the applicant plans to do his secondment, and the applicant is familiar with this instrument from his work at Yale’s Immunobiology Department. Dr. Vales (Host of the applicant) and Dr. Spaniel at the NIMH have funding to pursue these activities.
Ambitiousness of the project
We propose to target a significant, unresolved medical problem that should help manage patients with schizophrenia. This problem has not been sufficiently studied, and we suggest producing foundational data using an excellent recourse for clinically very well-characterized patients with schizophrenia, employing complex cell culture techniques of multiple cell types and involve -omics techniques. To our knowledge, such analyses have yet to be done in patients with TRS. These foundational data will then be used to select TRS's most significant and reliable markers and create a focused, cost-effective panel accessible to psychiatrists managing such patients. In turn, a part of this journey will be the large-scale data validation, which the ESO biobank enables, and the commercialization of the validated panel.

1.2 Soundness of the proposed methodology (including interdisciplinary approaches, consideration of the gender dimension and other diversity aspects if relevant).
METHODOLOGY
Prior use of blood cells as sensors
Two groups have used a genomics approach to evaluate inflammatory factors in sera from patients with autoimmune diseases. In one study, serum from patients with SLE was capable of maturing monocytes from normal, healthy donors into myeloid DCs, that upregulated maturation markers, such

as CD80, CD86, MHC class II, and could induce a strong mixed lymphocyte reaction (MLR) in culture (8). It was further shown using blocking antibodies, that the soluble factor responsible for promoting monocyte maturation was IFNA. This cytokine was not produced solely by CD123+ plasmacytoid DCs, which were markedly decreased in SLE sera, but also by another PBMC cell subtype. In another study by the same group, PBMC from normal donors were incubated with sera from SOJIA (systemic onset juvenile idiopathic arthritis) and control patients, and gene expression profiling was used to evaluate the PBMC transcriptome. Interestingly, a strong IL1B signature was found in SOJIA sera compared to controls. Treatment with an IL-1 receptor antagonist (Anakinra, Amgen Inc) was able to reduce clinical symptoms in most patients (9). Another group has used the same experimental model for T1DM {Wang, 2008 #9, and identified a molecular signature of 68 well annotated genes, upregulated only by sera from patients, and not by sera from long standing diabetes patients of by healthy controls. The authors also analyzed three longitudinal sample series, and detected the same molecular signature as early as 3 to 5.5 years before diabetes onset. This observation forms the basis of our proposed Aim 1 study, in which we will search for an early molecular signature in sera from dozens of T1DM at risk patients and controls, that were followed in their prediabetic stage for years, as part of a previous clinical study performed by our collaborator.
Objective 1/WP1
Source of plasma tested for its impact on sensors
Plasma samples will be obtained from the biobank formed during the prospective, longitudinal study “ESO” led by Dr. Filip Spaniel, who is a close collaborator of Dr. Karel Vales.
Patient population and healthy control subjects. The ESO study enrolls patients with first episode psychosis (FEP), men and women of age 18 to 60 years, who are recruited at 30 psychiatric inpatient facilities in Czech Republic, thus controlling a catchment area of 6.5 million people. At each study visit, participants undergo a complex examination that is repeated at intervals over subsequent years. The longitudinal study comprises three consecutive visits: Baseline visit V1 (in average 3 months after the disease onset). The initial sample group is re-examined one year after the baseline (visit 2, V2) and the same complex examination is repeated 4 years after V1 (Visit 3, V3). In the study proposed here, we will focus on V1 and V2. During each visit, an intensive MRI examination is performed (3T MRI scanner: MP-RAGE, DTI, H1-MRS, fMRI with self-reference activation paradigm, resting state fMRI) along with cognitive testing, blood sampling and clinical measures (PANSS, GAF, WHOQOL - BREF). Healthy controls are individuals of similar age, who do not suffer any mental disorder, including organic mental disorder and their first-degree relatives also do not suffer a major mental disorder. They undergo same evaluation as the patients.
Blood sampling and processing. Peripheral blood samples were obtained from fasting subjects between 7:00 am and 9:00 am. Eight ml of peripheral blood was drawn by venipuncture. For the plasma collection, the blood was centrifuged (1500 x g, 10 min) and the plasma was extracted with a pipette. Each samples was carefully mixed prior aliquating to assure homogeneous distribution of particles within plasma. These samples are stored in 330µl aliquots at −70 °C. Freeze-thawing cycles are carefully avoided, and if unavoidable, the details of such circumstances are recorded.

Sensors to test the impact of plasma from treatment-responsive and TRS patients
We will employ blood cells from a healthy donor as well as primary brain cells (neurons, astrocytes, microglia and oligodendrocytes). All these cells are commercially available, for example from accegen.com. Initially, RNA sequencing will determine the impacts of patient serum on healthy donor’s PBMC or brain cells, but later the experiments can employ QPCR panel that will be designed to address cell metabolism, and additional genes, pending pilot results from RNAseq.
Cell culture, and RNA processing, array hybridization in sensor cells
(a) Cell culture. Human leukocytes or primary brain cells were obtained from the Component Laboratory of New York Blood Center (Long Island City, NY). To separate mononuclear cells (PBMC), the leukocytes were diluted by adding three volumes of PBS and centrifuged on gradient of Ficoll-Paque PLUS (GE Healthcare Bio-Sciences AB, Uppsala, Sweden) at 800g for 30 min. After two washes with PBS, cells were counted, aliquoted at 1x107/vial and stored in liquid nitrogen. For cell culture, one vial was divided into 24 wells of a 48-well plate, in RPMI medium with human serum at 20%. Prior to use, serum samples stored frozen in -80oC freezer were thawed, vials were centrifuged for 1-2min at 14,000rpm in a microfuge to pellet insoluble material, and only the soluble fraction was used for experiments. Cultures were incubated in a CO2 incubator (5%CO2 in air, 37oC) for 6hrs, prior to RNA extraction. To reduce experimental variation, all samples are processed simultaneously (b) RNA processing and. RNA seq.
After cell culture for 6 hours, media is removed and cells are lysed with RLT buffer (Qiagen, RNeasy kit). RNA is prepared according to the provided protocol. 300-500ng RNA from each sample are further amplified and biotin-labeled with the “Illumina TotalPrep” RNA Amplification Kit (Ambion Inc). We routinely obtain 30-50ug labeled cRNA from one sample. 2ug of each cRNA is placed in 11ul ultrapure water and sent to the Yale Keck facility for RNAseq processing.
Statistical analyses
Differential Expression Analysis, Pathway Gene and Set Enrichment Analysis, and Network Analysis will be employed.
Objective 2/WP2
Blood cells from treatment-responsive and TRS patients to be exposed to antipsychotics
The current ESO biobank has plasma samples, but does not include PBMC. We will need to establish peripheral blood mononuclear cells (PBMC) collection from blood samples that are already being collected. The blood will carefully loaded on a lymphocyte separation medium, span for 30 min at 400g. Then the buffy coat is collected, washed twice, and the final pellet resuspended at ice cold freezing medium, place on dry ice for two hours, and then stored long-term in liquid nitrogen.
These cells will be placed in cell cultures and exposed to selected anti-psychotics. These cells will be placed in culture with therapeutic concentration. We will select several anti-psychotic to which our patients were resistant and test them individually in separate cell culture wells in cells from responsive versus resistant patients. After 6-12 hours (which will be decided after pilot tests before setting these assays), cells will be harvested and RNA sequencing will be performed selected cultures, and then we progress to test a group of genes in QPCR in all the experimental conditions. We will search for specific transcriptome changes that my explain resistance to the drug. Statistical analyses will involve tests used in Objective 1.

Objective 3/WP3
Objectives 1 and 2 will inform us about most important candidate pathways and will also guide the number of subjects involved in Objective 3 by calculation of statistical power. We will include gene expression detected by QPCR and intracellular and cell surface proteins detected by FACS. These analyses will form a foundation for future even larger validation for clinical use.
Objective 4/WP4
The ESO database involved large amounts of information about each participants. Our data will be integrated into the database and maps relating individual factors will be created.
INTERDISCIPLINARY APPROACHES
The project spans several disciplines: it employs pharmacological approaches, advanced cell biology techniques (e.g.co-cultures, FACS) and biochemical -omics analyses on clinical samples of patients with schizophrenia. Furthermore, data analyses about each patient the ESO databank will be integrated with data of colleagues and the NIMH. To name few of them, the information will include brain imaging, analyses of exosomes, comprehensive analysis of steroids and the activity of autonomic nervous system.
GENDER DIMENSION
Female and male patients are affected by schizophrenia about equally, though the mechanisms leading to the disorder may be gender depended (6). Considering gender differences specifically in TRS, it inflammatory status with elevation of interleukin-6 levels was more pronounced in female patients (10).Taken together, we will bear the gender differences in mind, and test gender-balanced groups, which enables us to make male: female comparisons to define gender-related mechanistic differences.
DIVERSITY ASPECTS
Demographic information, including socio-economic status, race or ethnicity will always be included in our analyses. Initially, in small sets of samples, these considerations may not be feasible. However, at the expansion phase, when we will test selected markers on a large population using the ESO biobank, we will be take diversity considerations into account.
1.3 Quality of the two-way transfer of knowledge between the researchers and the host.
HOW THE RESEARCHER WILL GAIN NEW KNOWLEDGE AND SKILLS
The applicant is a translational and interdisciplinary physician-scientist with interest in generating diagnostic markers for multiple brain conditions. Working with the team of Dr. Vales enables his access to a very large collection of samples of patients with schizophrenia which makes it possible not only to explore various mechanisms of the disease, but also validation of data on a large scale. The applicant is interested in commercial development of research data.
RESEARCHER’S TRANSFER OF THE PREVIOUSLY ACQUIRED KNOWLEDGE TO THE HOST
The applicant is a physician-scientist with significant track-record in genetics, molecular biology and immunology. He will bring the “know-how” to many techniques applicable to translational research,

and train personnel in the lab. He focuses on molecular mechanisms of brain malformations and of intracranial tumors in patients with a variety of DNA mutations. His goal, similarly to investigators at the NIMH, is to find subsets of patients with different mechanisms leading to these diseases and their responsiveness to treatment. To this end, he built hands-on experience with employing state-of-the-art Next-Gen Sequencing technologies, such as RNA-seq, miRNA-seq, Single-cell RNA-seq, ChIP-seq, Whole Exome sequencing WES, Whole Genome sequencing WGS, Genotyping GWAS studies, ChIP- seq, Illumina methylation arrays, and others. To study proteins and/or their interactions we are using Western blot, immunofluorescence assays and Luminex technology. He also designed custom Luminex assays to study intracellular proteins and protein interactions. He has extensive experience with recombinant DNA technology, gene expression, mutagenesis and functional assays such as Luciferase-based. Dr. Henegariu would be interested in building a core facility for genetic and epigenetic analyses at the NIMH in Czechia.
1.4 Quality and appropriateness of the researcher’s professional experience, competences & skills.
The applicant a physician-scientist with a track record in molecular biology, genetics and immunology. He obtained his M.D. degree in Cluj, Romania, and a Ph.D. degree in genetics at Heidelberg University, Germany before coming to Yale University. He has hands-on experience with multiple molecular techniques, including molecular cytogenetic techniques, such as FISH, preparation of DNA arrays, gene/cDNA cloning (particularly Gateway cloning technology, and seamless cloning), PCR mutagenesis and gene functional analysis, non-commercial development of Luminex assays for specific protein quantification. currently focuses on developing new molecular tools for diagnosis of brain tumors. H-index 33, number of publications 88, cited 10,854 times
2. IMPACT
2.1 Credibility of the measures to enhance the career perspectives and employability of the researcher and contribution to his/her skills development.
The applicant is a faculty member at the Yale School of Medicine in the U.S.A. He wishes to return to Europe, where he maintained his professional and social network, including his home country, Romania, Germany, and Czechia. He is motivated to pursue basic and translational biomedical research with commercial applicability and forming start-ups for diagnostic markers. Extensive data collections and samples, such as the E.S.O. collection at the NIMH, are of great interest to his pursuits. He wants to organize a Genetic and Epigenetic Core Facility at the NIMH. Concerning the start-up establishment, the applicant’s hosts, Dr. Karel Vales, and Filip Spaniel, are currently setting up their first start-up. They work with a consultant Dr. John Normanton, a neuroscientist who has a long track record of successful start-ups with his company Oxanindia Ltd., U.K.
2.2 Suitability and quality of the measures to maximise expected outcomes and impacts, as set out in the dissemination and exploitation plan, including communication activities.
Expected outcomes are five peer-reviewed publications and one or more patents.

Data from our research will be disseminated at three levels: 1) the general public, 2) physicians and medical students, and 3) scientists from multiple disciplines. Concerning the general public, we will present at the yearly gathering organized by the Czech Academy of Sciences, “Science trade fair,” a three-day festival about scientific discoveries for a broad public. We will contact high school teachers to facilitate interactions between high school students, postdocs, or graduate students that may affect their career choices. Concerning physicians and medical students, the applicant plans on teaching at the 3rd Medical School of Karlova Univerzita and will incorporate the research findings in his lectures. We will also participate actively in professional meetings that target psychiatrists, immunologists, and general practitioners of the Czech Republic. As to the interdisciplinary scientific community, we will present our data at workshops (e.g., Gordon conference) and large professional meetings (e.g., Annual Meeting of American Psychiatric Association with >13,000 attendees).
Regarding an exploitation plan, we will patent any feasible outcomes and support the formation of new start-up companies that will transfer new findings into a commercial sphere and make them available to physicians and their patients, as described above (end of the paragraph in 2.1.)
To maintain the balance between intellectual property and open science principles, the applicant will regularly consult with the Center of technology transfers led by his host, Dr. Vales at the NIMH. The Data management plan will guide data handling and archiving while respecting the rules of open science, ethical aspects of data handling, and FAIR (Findable, Accessible, Interoperable, and Reusable) principles in both institutions. The primary data in this project consists of a correlation between clinical data and data from NGS and Q-PCR. To ensure transparency and openness, the project will adhere to the principles of open science. We will fully adopt the FAIR data management policy for all data collected during the project.
2.3 Sustainability of the candidates’ research project in the Region.
The project's sustainability is supported by the association with the NIMH in Czechia, one of the country's top research and training institutions linked closely to the 3rd Faculty of Medicine, Charles University in Prague. Concerning the societal impact of the project, the NIMH is located in the Region, which per se enhances awareness about psychiatric conditions. The outcomes of this project may spearhead similar approaches to resolve the diagnosis and treatment of other psychiatric conditions, rendering the Region more visible for its scientific impact. Concerning opportunities to continue the research in the Region, the applicant's goal is to establish an interdisciplinary research group. He has already collaborated (and published together) with Dr. Kawikova, who is his Yale colleague and has ties to the NIMH. Technology transfer of the data may lead to one or more start-up companies. Such efforts will have an economic impact on the Region. The applicant will maintain his broad international network of collaborators while residing in the region.
3. IMPLEMENTATION
3. 1 Quality and effectiveness of the work plan and assessment of risks
Objectives 1-4 outlines in the chapter 1.2. correspond to work packages (WP) in the Gantt chart above. Time line of the effective approach to resolution of individual Activities in Objectives is also evident. The assays are straightforward and the applicant has extensive experience with testing patient serum on PBMC sensors. A risk that needs to be anticipated is the fact that PBMS sensors may be sometimes

highly sensitive to tested plasma sample, which results in a high background. In such cases, it is necessary to find an alternative approach. One possibility is to select a component of plasma that is of highest interest, and apply it to sensor cells. Such component could be exosomes, which a re nanovesicles containing coding and non-coding RNA, proteins and lipids, and that the group at the NIMH is starting to study. This would reduce the impact of plasma in its full complexity but it would be still a very informative alternative approach.


3.2. Relevance, feasibility and benefit the planned secondment
The applicant is planning two secondments. The first will be in the Institute of Organic Chemistry and Biochemistry in Prague, Czech Republic. There active collaborative efforts with the NIHM addressing medicinal chemistry and development of diagnostic tools that will now applied for TRS. They will assist with the development of diagnostic tools, employ their expertise in analyses and synthesis of complex molecules, and help optimize development of a diagnostic panel that we anticipate to be the outcome of the efforts in the project. This secondment fulfills the principle of interdisciplinarity.
The biotech company C2P Nexars is currently building new molecular and biochemical laboratories and production facilities for biotechnology and molecular productions. Motivation for a secondment in this company is development of the diagnostic panel into a commercial product. This secondment fulfills the criterium of intersectorality.
REFERENCES

1. Patel, K. R., J. Cherian, K. Gohil, and D. Atkinson. 2014. Schizophrenia: overview and treatment options. P T 39: 638-645.
2. Correll, C. U., and O. D. Howes. 2021. Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options. J Clin Psychiatry 82.

3. Kane, J. M., O. Agid, M. L. Baldwin, O. Howes, J. P. Lindenmayer, S. Marder, M. Olfson, S. G. Potkin, and C. U. Correll. 2019. Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia. J Clin Psychiatry 80.
4. Suzuki, T., G. Remington, T. Arenovich, H. Uchida, O. Agid, A. Graff-Guerrero, and D. C. Mamo. 2011. Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia. Br J Psychiatry 199: 275-280.
5. Shah, P., Y. Iwata, E. Plitman, E. E. Brown, F. Caravaggio, J. Kim, S. Nakajima, M. Hahn, G. Remington, P. Gerretsen, and A. Graff-Guerrero. 2018. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review. Psychiatry Res 268: 114-122.
6. Brand, B. A., J. N. de Boer, P. Dazzan, and I. E. Sommer. 2022. Towards better care for women with schizophrenia-spectrum disorders. Lancet Psychiatry 9: 330-336.
7. Jiao, S., T. Cao, and H. Cai. 2022. Peripheral biomarkers of treatment-resistant schizophrenia: Genetic, inflammation and stress perspectives. Front Pharmacol 13: 1005702.
8. Blanco, P., A. K. Palucka, M. Gill, V. Pascual, and J. Banchereau. 2001. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294: 1540-1543.
9. Pascual, V., F. Allantaz, E. Arce, M. Punaro, and J. Banchereau. 2005. Role of interleukin-1 (IL-
1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL- 1 blockade. J Exp Med 201: 1479-1486.
10. He, J., Y. Wei, J. Li, Y. Tang, J. Liu, Z. He, R. Zhou, X. He, H. Ren, Y. Liao, L. Gu, N. Yuan,
X. Chen, and J. Tang. 2023. Sex differences in the association of treatment-resistant schizophrenia and serum interleukin-6 levels. BMC Psychiatry 23: 470.

Zápis z jednání Steering Committee MERIT ze dne 11.12.2023

Přítomni:
· VYMAZÁNO 

Agenda:
1. Zahájení, schválení programu schůze Program schůze:
· Rekapitulace stavu úkolů z minulého jednání
· Představení výběrového procesu
· Schvalování předložených projektů
· Termíny následujících jednání + zamyšlení nad informacemi potřebnými pro monitoring vědeckých projektů

Návrh usnesení:
Řídicí komise MERIT bere na vědomí program jednání.
Výsledky hlasování Pro: 4; Proti: 0 Přijaté usnesení:
Řídicí komise MERIT bere na vědomí program jednání.


2. Úkoly z minulého jednání
· Vytvořeno sdílené úložiště pro členy SC v prostředí Microsoft 365
· Aktualizovaný jednací řád a seznam zúčastněných partnerských institucí programu MERIT poslán členům SC
· Připravena Dohoda o mlčenlivosti (Non-disclosure agreement) kvůli zajištění důvěrnosti informací členů Steering Committee, podepsána všemi členy (přílohy tvořily ještě prohlášení v AJ: Prohlášení o důvěrnosti, neexistenci střetu zájmů a nediskriminaci, kvůli splnění podmínek projektu vůči EU)

Návrh usnesení:
Řídicí komise MERIT bere na vědomí stav úkolů z minulého jednání.

Výsledky hlasování Pro: 4; Proti: 0
Přijaté usnesení: Řídicí komise MERIT bere na vědomí stav úkolů z minulého jednání.


3. Stručné představení výběrového procesu
· PPT prezentace Programové manažerky

Návrh usnesení:
Řídicí komise MERIT bere na vědomí informaci o průběhu výběrového procesu první výzvy programu MERIT.
Výsledky hlasování Pro: 4; Proti: 0
Přijaté usnesení: Řídicí komise MERIT bere na vědomí informaci o průběhu výběrového procesu první výzvy programu MERIT.

4. Schvalování předložených projektů
· Členům komise byla předem sdílena tabulka s přehledem kandidátů, jejich umístění, včetně navrhovaných secondmentů, stručné abstrakty řešených projektů, a dále kompletní projektové návrhy a hodnotící reporty z obou kol hodnocení
· Všechny projekty prošly hodnocením v mezinárodním transparentním výběrovém řízení v souladu s pravidly programu MERIT.

Návrh usnesení:
Řídicí komise schvaluje celkem 23 projektů předložených do první výzvy programu MERIT, z nichž 15 projektů, které získaly v hodnocení nejvyšší skóre, budou podpořeny, a 8 rezervních projektů může být podpořeno v případě, že některý z podpořených projektů nebude realizován.
Výsledky hlasování Pro:4 ; Proti: 0
Přijaté usnesení – Řídicí komise schvaluje celkem 23 projektů předložených do první výzvy programu MERIT, z nichž 15 projektů, které získaly v hodnocení nejvyšší skóre, budou podpořeny, a 8 rezervních projektů může být podpořeno v případě, že některý z podpořených projektů nebude realizován.
Řídící komise zároveň navrhuje prověřit zejména ruské žadatele a žadatele z třetích  zemích  z důvodu bezpečnostního rizika realizace jejich projektů (BIS).

5. Plán pro druhou výzvu a termíny následujících setkání
· ČERVENEC 2024 – monitoring po prvním reportovacím období (zprávy o průběhu realizace projektů, komunikační a diseminační aktivity vědců, účast vědců na akcích SIC apod.)
· ZÁŘÍ 2024 – schvalování projektů vybraných v druhé výzvě programu

· LEDEN 2025 – monitoring po druhém reportovacím období (zprávy o průběhu realizace projektů, komunikační a diseminační aktivity vědců, účast vědců na akcích SIC apod.)

Návrh usnesení:
Řídicí komise MERIT bere na vědomí plán pro druhou výzvu programu a termíny následujících jednání.
Výsledky hlasování Pro:4; Proti: 0 Přijaté usnesení
Řídicí komise MERIT bere na vědomí plán pro druhou výzvu programu a termíny následujících jednání. Řídíce komise stanovila termín na příští setkání k prvnímu reportovacímu období dne 25.7.2024.

6. Zamyšlení nad informacemi potřebnými pro monitoring projektů
· Monitoring bude probíhat jednou za 6 měsíců, informace budou pravidelně poskytovány ze strany výzkumných organizací (supervizor + vybraný stážista)

Návrh usnesení:
Řídicí komise MERIT bere na vědomí obsah monitorovacího reportu a schvalují navržené změny.
Výsledky hlasování Pro:4.; Proti:0 Přijaté usnesení
Řídicí komise MERIT bere na vědomí obsah monitorovacího reportu a schvaluje navržené následující změny, které budou vloženy do monitorovacího reportu:
· neúspěchy a případné změny projektu,
· informace, zda je projekt v souladu s harmonogramem,
· informace o tom, v jakém stavu se projekt nachází,
· milníky projektu.
Monitorovací Report bude upraven a poslán Řídicí komisi k odsouhlasení.

Zapsala:	Zápis ověřil:
VYMAZÁNO	VYMAZÁNO
Programová manažerka MERIT	Předsedající Steering Committee

Příloha: Seznam schválených projektů

Seznam 15 kandidátů s nejvyšším skóre

	
Name of the candidate
	

Host organisation
	

Final score

	VYMAZÁNO
	ELI Beamlines Facility - The Extreme Light Infrastructure ERIC
	
95,8

	VYMAZÁNO
	Institute of Animal Physiology and Genetics of the Czech Academy of Sciences
	
95,7

	VYMAZÁNO
	
National Institute of Mental Health
	
94,7

	VYMAZÁNO
	
Astronomical Institute of the Czech Academy of Sciences
	
89,9

	VYMAZÁNO
	
Astronomical Institute of the Czech Academy of Sciences
	
89,7

	VYMAZÁNO
	Institute of Animal Physiology and Genetics of the Czech Academy of Sciences
	
87,8

	VYMAZÁNO
	Institute of Thermomechanics of the Czech Academy of Sciences
	
85,6

	VYMAZÁNO
	
Astronomical Institute of the Czech Academy of Sciences
	
84,1

	VYMAZÁNO
	ELI Beamlines Facility - The Extreme Light Infrastructure ERIC
	
83,3

	VYMAZÁNO
	
Czech University of Life Sciences Prague
	
82,3

	VYMAZÁNO
	Institute of Physics of the Czech Academy of Sciences / HiLASE
	
81,5

	VYMAZÁNO
	Czech Technical University in Prague, Czech Institute of
Informatics, Robotics, and Cybernetics
	
81,4

	VYMAZÁNO
	Research Institute of Geodesy, Topography and Cartography
	
81,1

	VYMAZÁNO
	Institute of Physics of the Czech Academy of Sciences /
HiLASE
	
80,1

	VYMAZÁNO
	UCEEB Czech Technical University in Prague, University
Centre for Energy Efficient Buildings
	
78,9

Seznam 8 rezervních kandidátů

	Name of the
candidate
	
Host organisation
	
Final score

	VYMAZÁNO
	
National Institute of Mental Health
	
76,8

	VYMAZÁNO
	
Institute of Microbiology of the Czech Academy of Sciences
	
76,1

	VYMAZÁNO
	
Research Institute of Geodesy, Topography and Cartography
	
76,1

	VYMAZÁNO
	
Astronomical Institute of the Czech Academy of Sciences
	
74,7

	VYMAZÁNO
	UCEEB Czech Technical University in Prague, University Centre for Energy Efficient Buildings
	
74,6

	VYMAZÁNO
	
National Institute of Mental Health
	
74,5

	VYMAZÁNO
	Institute of Animal Physiology and Genetics of the Czech Academy of Sciences
	
73,8

	VYMAZÁNO
	
ELI Beamlines Facility - The Extreme Light Infrastructure ERIC
	
73,6

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