Cell-Cell Communications and Tissue Memory in Vitiligo

白癜风的细胞间通讯和组织记忆

• 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
• 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

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：细胞间通信 通过分子分泌或直接细胞接触进行的细胞间通讯使细胞能够感知和 对组织内的细胞外环境做出反应；这些沟通是关键决策的基础 与发育、组织稳态和免疫有关。信号传输中的错误可能会导致一系列问题 疾病，包括自身免疫性疾病，因此提高了对细胞间通讯以及如何进行通讯的了解 他们对疾病的困扰可能有助于开发改进的治疗方法。 白癜风是一种皮肤自身免疫性疾病，其中 T 细胞靶向产生色素的黑素细胞， 导致毁容的白斑，对于深色皮肤的人来说尤其具有破坏性。白癜风是一种理想的治疗方法 自身免疫性疾病，需要研究细胞间信号传导，因为它很常见，并且皮肤容易接触到 使用转化研究方法进行观察和抽样。我们探索白癜风的信号通路 利用单细胞RNA测序（scRNA-Seq），发现白癜风皮损皮肤细胞反映多样化 表型。我们利用这些数据生成了全面的细胞图谱，该图谱揭示了数百个 白癜风病变皮肤中的信号分子和受体失调。 推动该项目的首要假设是疾病进展需要复杂的细胞 协调自身免疫的通信，并且由这些信号建立的表观遗传记忆是 造成复发的责任。我们的目标是剖析和验证我们已识别的蜂窝通信 从 scRNA-Seq 中确定它们促进和维持自身免疫的功能，然后重新组装它们 全面了解白癜风发病机制和皮肤内的自身免疫记忆。我们将 首先确定细胞通讯失调如何影响黑素细胞-T 细胞相互作用 我们的初步数据揭示了三种新颖的信号传导途径。接下来，我们将定义记忆形成 角质形成细胞通过在病变中经历染色质重塑的细胞类型特异性区域。最后，我们将 利用体外趋化因子刺激皮肤细胞来确定新型趋化因子和非经典趋化因子的作用 信号传导影响白癜风的细胞功能，以及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。 完成拟议的研究后，我们期望发现免疫的基本机制 细胞靶向自身组织并直接在组织内促进自身免疫的长期记忆，这可以 不仅对白癜风有影响，而且对其他破坏性自身免疫性疾病也有影响。