"Indanio Fellowship Year Two *Renewal, previous title ""Indanio Fellowship"""

The proposed project goals are five fold:

1) Generate and lead initiatives in drug discovery especially in the area of target identification/validation.

2) Generate transgenic zebrafish lines for nuclear receptor diseases related to oncology and metabolic diseases

3) Apply and supervise drug discovery on nuclear receptor ligand trap fish lines in the area of metabolic disease / cancer to extend state of the art research that leads to the discovery of new therapies

Development of 3D culture reagents and scoring systems for assays of normal andmalignant epithelial stem cells Year Two

The overarching objective of this proposal is to develop and validate a new, robust and reproducible 3D culture system that supports the clonal growth of primary sources of normal and malignant human epithelial cells and that is suitable for commercialization by STEMCELL Technologies who will partner in its development. The work will systematically address 3 Specific Aims.

Phase I: Using simultaneous EEG-fMRI to study theaffective mechanisms underlying obsessivecompulsivedisorder

The aim of this project is to improve simultaneous EEG-fMRI techniques through the use of constrained principal component analysis (CPCA). The main problem with combining EEG measures and fMRI measures is that recording EEG in the MR scanner always injects noise into the data. CPCA partitions the variability of the data into systematic and error variance.

Translating knowledge about optimization of surgical recovery into achieved outcomes forpatients: A dismantling trial in colorectal surgery

This study will be a three-arm, dismantling randomized trial aimed to assess the extent to which recovery after colorectal surgery is influenced by postoperative facilitation of nutrition and mobilization. Adult patients (> 18 years) with colonic or rectal diseases planned for colorectal resection at the Montreal General Hospital will be considered for inclusion. Criteria for exclusion will be: metastatic disease, medical conditions that preclude adequate postoperative feeding and/or mobilization (e.g.

Developmental potential of oocytes after cryopreservation

Overall aim of the project: To establish the protocol for oocyte cryopreservation which results in a high success rate of embryo development. We will first use mouse oocytes to test the effects of various compounds supplemented in the cryopreservation medium on subsequent oocyte competence. The mouse has been useful model for elucidating various aspects of oogenesis and reproductive development events including, global oocyte gene expression, intra-oocyte redox state, and critical events during meiotic initiation in the ovary, follicle formation and oocyte growth and maturation.

Assessment and selection of competent oocytes for embryo development

Research project aims:

1) To capture and compare microRNA (MIR) signatures in mouse ovarian follicular fluid and spent media of cumulous cells-oocyte complexes (COCs) isolated from infertility mouse models to identify one or more unique MIR signatures that will distinguish competent oocytes from incompetent oocytes.

Development of therapeutic peptides to treat bacterial and viral infections

Peptide therapeutics are a novel approach to treat bacterial and viral infections, which have major advantages over small molecules. Peptide molecules have been used previously to treat HIV infections, and I have previously shown that peptide molecules targeting Chlamydia can prevent infection in vivo. Project Objectives: 1. To take previously characterized peptides, move them onto an HSA scaffold, and evaluate their expression in a yeast system. 2. To test the HSA scaffold therapeutic peptides in vitro against Chlamydia infection, RSV infection, and influenza infection. 3.

Design and Synthesis of Specific Inhibitors of CYP26 for Blocking Retinoic Acid Metabolism: A Safer Approach to Retinoid Therapy for Skin Disease

OBJECTIVE; We will advance our development of novel specific inhibitors of the retinoic acid (RA) metabolizing P450 enzymes, CYP26A1 and CYP26B1, to treat skin disorders - an approach that will have significant safety advantages over current retinoid therapies. These inhibitors will be used primarily to target cystic acne but will also be evaluated for their therapeutic potential in treating other skin disorders including actinic keratosis, rosacea, oral leukoplakia and skin cancer.

Indanio Fellowship

My objectives will be 1) to establish stable zebrafish lines expressing the human nuclear receptors not yet established by Indanio; 2) to de-orphanize at least three human nuclear receptors; 3) to lead initiatives in drug target identification and validation; and 4) to establish protocols for structural and pharmacokinetic analysis of potential drug targets. 1) Establishing the zebrafish lines will be accomplished using the Indanio-designed reporter system and standard molecular biology techniques. 2) The strategy to adopt orphaned nuclear receptors is a multistage project.

Development and Evaluation of a Life Threatening Illness Point-of-Care Triage Test for the Fionet System

Building on our previous research and POC test prototype development, our goals for the project are to: 1) to confirm and further validate the association of altered levels of endothelial biomarkers with disease severity and mortality outcomes from LTIs in large patient populations in two settings, and 2) develop a rapid POC triage test for their detection at the bedside.

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