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Cell-Cell Communications and Tissue Memory in Vitiligo

白癜风的细胞间通讯和组织记忆

基本信息

批准号：
10703386
负责人：
Manuel Garber
金额：
$ 57.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703386
关键词：
3-Dimensional Acceleration Acute Affect Autoimmune Autoimmune Diseases Autoimmunity Biological Assay Bulla CD8-Positive T-Lymphocytes CXCL9 gene Cell Communication Cell Culture Techniques Cell physiology Cells Cellular Assay Center for Translational Science Activities Chromatin Chromatin Structure Communication Complex Data Development Disease Disease Progression Environment Epigenetic Process Event Flow Cytometry Genes Genomics Homeostasis Immune Immunity In Vitro Intercellular Fluid Knowledge Lesion Ligands Liquid substance Location MCHR1 gene Maps Measures Memory Modeling Modification Pathogenesis Pathway interactions Patients Phenotype Pigments Recombinant Chemokine Recurrent disease Relapse Research Research Methodology Resolution Sampling Signal Pathway Signal Transduction Signaling Molecule Skin Suction T-Lymphocyte TGFB2 gene Techniques Tissues Transforming Growth Factor Beta 2 Translational Research Transposase Vitiligo White Spots cell type chemokine chromatin remodeling cytokine data communication epigenetic memory experience extracellular improved in vitro Model in vivo insight interest keratinocyte long term memory melanocyte migration multiple omics novel prevent receptor single-cell RNA sequencing skin disorder three dimensional cell culture transcriptomics

项目摘要

Project 2: Cell-cell communications Cell-to-cell communication via the secretion of molecules or direct cell contact allows cells to perceive and respond to the extracellular environment within a tissue; these communications underlie critical decisions related to development, tissue homeostasis, and immunity. Errors in signaling can result in a range of diseases, including autoimmune disease, so improved understanding of cell-to-cell communications and how they are perturbed in disease may allow for the development of improved treatments. Vitiligo is an autoimmune disease of the skin in which T cells target pigment-making melanocytes, which results in disfiguring white spots that are particularly devastating for those with darker skin. Vitiligo is an ideal autoimmune disease in which to study intercellular signaling because it is common, and the skin is accessible to observation and sampling using translational research methods. We explored signaling pathways in vitiligo using single cell RNA sequencing (scRNA-Seq) and found that vitiligo lesional skin cells reflect diverse phenotypes. We used this data to generate comprehensive cellular maps, which revealed that hundreds of signaling molecules and receptors are dysregulated in vitiligo lesional skin. The overarching hypothesis that drives this project is that disease progression requires complex cellular communications to coordinate autoimmunity, and that epigenetic memory established by these signals is responsible for relapse. Our objective is to dissect and validate cellular communications that we have identified from scRNA-Seq, determine their function to promote and maintain autoimmunity, and then reassemble them into a comprehensive understanding of vitiligo pathogenesis and autoimmune memory within the skin. We will first determine how dysregulated cellular communications affect melanocyte-T cell interactions by focusing on three novel signaling pathways revealed in our preliminary data. Next, we will define memory formation in keratinocytes through cell type-specific regions that undergo chromatin remodeling in lesions. Finally, we will use in vitro chemokine stimulation of skin cells to determine how novel chemokines and non-classic chemokine signaling affects cell function in vitiligo, as well as their long-term impact on epigenetic memory. We will integrate this understanding with spatial information revealed by the seqFISH+ Research Core. Upon completion of the proposed research, we expect to discover fundamental mechanisms by which immune cells target self-tissues and promote long-term memory of autoimmunity directly within the tissue, which could have implications not only for vitiligo but other devastating autoimmune diseases.

项目2：细胞-细胞通讯