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：细胞通信通过分子的分泌或直接细胞接触的细胞对细胞通信使细胞可以感知和应对组织内的细胞外环境；这些沟通是关键决定的基础与发育，组织稳态和免疫力有关。信号传导中的错误可能导致一系列包括自身免疫性疾病在内它们在疾病中受到干扰，可能会允许发展改进的治疗方法。白癜风是皮肤的一种自身免疫性疾病，其中T细胞靶向色素生物黑素细胞，该疾病是一种皮肤的疾病导致毁容的白点，对于皮肤较深的人来说，这尤其是毁灭性的。白癜风是理想的自身免疫性疾病在其中研究细胞间信号，因为它很常见，并且可以使用皮肤使用翻译研究方法观察和采样。我们在白癜风中探索了信号通路使用单细胞RNA测序（SCRNA-SEQ），发现白癜风病变的皮肤细胞反映了多样表型。我们使用这些数据来生成全面的蜂窝图，这表明数百个信号分子和受体在白癜风病变的皮肤中失调。驱动该项目的总体假设是疾病进展需要复杂的细胞与协调自身免疫的通信，这些信号确定的表观遗传记忆是负责复发。我们的目标是剖析和验证我们已经确定的蜂窝通信从scrna-seq，确定其功能以促进和维持自身免疫性，然后重新组装全面了解皮肤内的白癜风发病机理和自身免疫记忆。我们将首先确定失调的细胞通信如何通过专注于黑素性细胞-T细胞相互作用我们的初步数据中揭示了三个新颖的信号通路。接下来，我们将在角质形成细胞通过细胞类型特异性区域，在病变中进行染色质重塑。最后，我们会的利用皮肤细胞的体外趋化因子刺激来确定新颖的趋化因子和非经典趋化因子如何信号传导会影响白癜风的细胞功能，以及它们对表观遗传记忆的长期影响。我们将将这种理解与SeqFish+研究核心揭示的空间信息相结合。拟议的研究完成后，我们希望发现免疫的基本机制细胞靶向自我组织，并直接在组织中直接促进自身免疫性的长期记忆，这可能不仅对白癜风，而且对其他毁灭性自身免疫性疾病有影响。