Penn TMC: Organ-Specific Project

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The female reproductive system—comprised of the uterus, fallopian tubes and the ovaries—undergoes some of the most dynamic changes in structure and function of any adult human organ system on a monthly basis and throughout life. Tissue organization in the female reproductive system is paramount as it is responsible for the coordinated cyclic changes necessary not only for reproduction but also for the maintenance of multiple other organ systems. Here, we propose to couple our unique access to the entire normal female reproductive system with our expertise in single cell biology to establish a multi- scale molecular map of the female reproductive system. We will collect and manage subject/donor samples to generate a multi-scale molecular map: We will leverage our subject/donor population to comprehensively sample up to 22 tissue locations from the same subject (16 donors), as well as sample a single tissue over a large number of donors to collect temporal information. In total, we propose to collect ~700 tissue samples over 22 locations from four female reproductive organs using multiple assay modalities. We will generate a spatially coordinated multi-scale molecular map: We will collect scRNAseq (3 different schemes), multiplex FISH (clampFISH), in situ open chromatin, as well as simultaneous RNA/open chromatin assays and protein assays in collaboration with other TMCs for a total of six different assay methods. We will also develop a 3D digital model of the female reproductive system using subject/donor imaging data, and develop associated spatial annotation tools to index our clinical sample collection in SA1 with anatomical coordinates. All assay data will be registered to our 3D anatomical map that will be integrated with the HIVE Common Coordinate Framework. All metadata from subject records, clinical procedures, molecular procedures, and informatics pipelines will be collected, curated, and deposited as structured data. We will use well-validated protocols (e.g., 10X Chromium platform) or validate and optimize molecular assays before moving them to production pipelines. We will work with other TMCs as well as other HuBMAP groups to develop community standards and validation methods for the molecular assays. For systematic data collection and production pipeline work, we will construct a streamlined process from Clinical Sampling, to 3D Model Indexing, to Molecular Assays, to Data Analysis and Coordination. The completion of our data collection activities will create an unprecedented public resource that will enhance our understanding of human reproductive biology and impact women’s health.