Cell-Cell Communications and Tissue Memory in Vitiligo

项目2：小区间通信 通过分泌分子或直接细胞接触进行的细胞间通信使细胞能够感知和 对组织内的细胞外环境做出反应；这些交流是关键决策的基础 与发育、组织动态平衡和免疫有关。信令中的错误可能会导致 疾病，包括自身免疫性疾病，因此提高了对细胞间通信的理解以及如何 他们受到疾病的困扰，可能会发展出更好的治疗方法。 白癜风是一种皮肤自身免疫性疾病，T细胞以产生色素的黑素细胞为靶细胞， 会导致白斑毁容，这对深色皮肤的人来说尤其具有破坏性。白癜风是一种理想的 自身免疫性疾病，研究细胞间信号，因为它是常见的，皮肤是可以接触到的 使用翻译性研究方法进行观察和取样。我们探索了白癜风的信号通路。 利用单细胞RNA测序(scRNA-Seq)发现白癜风皮损皮肤细胞反应多样 表型。我们使用这些数据来生成全面的细胞地图，这揭示了数百个 白癜风皮损中的信号分子和受体调节失调。 推动这个项目的最重要的假设是疾病的发展需要复杂的细胞 协调自身免疫的通讯，由这些信号建立的表观遗传记忆是 对旧病复发负责。我们的目标是剖析和验证我们已经确定的蜂窝通信 根据scRNA-Seq，确定它们促进和维持自身免疫的功能，然后对它们进行重组 全面了解白癜风的发病机制和皮肤内的自身免疫记忆。我们会 首先确定细胞通讯失调如何影响黑素细胞与T细胞的相互作用 我们的初步数据揭示了三条新的信号通路。接下来，我们将在 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定区域。最后，我们会 使用皮肤细胞体外趋化因子刺激来确定新的趋化因子和非经典趋化因子如何 信号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。我们会 将这一理解与seqFISH研究核心揭示的空间信息结合起来。 在拟议的研究完成后，我们预计将发现免疫的基本机制 细胞以自身组织为靶标，直接在组织内促进自身免疫的长期记忆，这可能 不仅对白癜风有影响，而且对其他破坏性的自身免疫性疾病也有影响。

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.