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: 10404446
• 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/10404446
• 关键词: 3-Dimensional; Acute; Affect; Autoimmune; Autoimmune Diseases; Autoimmunity; Back; Biological Assay; Bulla; CD8-Positive T-Lymphocytes; CXCL9 gene; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Cellular Assay; 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; 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; skin lesion; 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 通过分泌分子或直接细胞接触的细胞与细胞的通信允许细胞感知和 对组织内的细胞外环境做出反应;这些通信是关键决策的基础 与发育、组织稳态和免疫力有关。信号中的错误可能导致一系列 疾病，包括自身免疫性疾病，因此提高了对细胞间通讯的理解， 他们在疾病中的不安可能会允许开发改进的治疗方法。 白癜风是一种自身免疫性皮肤病，其中T细胞靶向制造色素的黑色素细胞， 导致毁容的白色斑点，这对那些皮肤较黑的人来说特别具有破坏性。白癜风是一种理想 研究细胞间信号传导的自身免疫性疾病，因为它很常见，而且皮肤可以接触到 使用转化研究方法进行观察和取样。我们探索了白癜风的信号通路 使用单细胞RNA测序（scRNA-Seq），发现白癜风皮损皮肤细胞反映了不同的 表型我们利用这些数据生成了全面的细胞图谱，结果显示， 信号分子和受体在白癜风皮损皮肤中失调。 推动这个项目的首要假设是，疾病的进展需要复杂的细胞 通信来协调自身免疫，并且由这些信号建立的表观遗传记忆是 负责复发。我们的目标是解剖和验证我们已经确定的细胞通信 从scRNA-Seq，确定它们促进和维持自身免疫的功能，然后重新组装它们， 从而全面了解白癜风的发病机制和皮肤内的自身免疫记忆。我们将 首先确定失调的细胞通讯如何影响黑素细胞-T细胞相互作用， 在我们的初步数据中揭示了三种新的信号通路。接下来，我们将定义记忆的形成， 通过在病变中经历染色质重塑的细胞类型特异性区域，刺激角质形成细胞。最后我们将 使用皮肤细胞的体外趋化因子刺激来确定新趋化因子和非经典趋化因子 信号传导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+ Research Core揭示的空间信息相结合。 在完成拟议的研究后，我们希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， 不仅对白癜风有影响，而且对其他毁灭性的自身免疫性疾病也有影响。