The Role of Adaptive and Innate Immunity for the Development of Aortic Valve Stenosis

心脏瓣膜疾病很普遍，大约10%的75岁及以上的人受到影响。最常见的疾病是主动脉瓣狭窄，由多因素引起。除了遗传易感性和代谢改变，免疫细胞和炎症过程驱动主动脉瓣退行性变的发生和进展。有趣的是，高达15%的所有瓣膜细胞是白细胞。该提案探讨了白细胞如何以及哪些白细胞在衰老过程中导致主动脉瓣退化。我们将使用最先进的技术探索瓣膜白细胞库的数量和质量变化，包括高维流式细胞术、测序方法以及最近开发的消除不同细胞亚群的小鼠模型。一个重要的重点将放在T淋巴细胞和骨髓白细胞的相互作用。最近开发的空间转录组学方法的应用将使我们能够检查病变瓣膜组织中的细胞-细胞相互作用。在使用人类组织的翻译方法中，我们将通过结合单细胞RNA测序和单细胞染色质可及性测定来评估细胞多样性和激活状态。拟议的实验将有助于完善我们对主动脉瓣退行性变期间发生的炎症过程的理解，并可能开辟新的精确的治疗途径。

Heart valve disorders are prevalent and affect approximately 10% of people 75 years and older. The most frequent disorder is aortic stenosis, caused by a multifactorial process. Next to genetic predispositions and metabolic alterations, immune cells and inflammatory processes drive the onset and progression of aortic valve degeneration. Interestingly, up to 15% of all valve cells are leukocytes. This proposal explores how and which leukocytes contribute to aortic valve degeneration during aging. We will explore numerical and qualitative alterations of the valve’s leukocyte pool using state-of-the-art technology, including high-dimensional flow cytometry, sequencing methods, and recently developed mouse models that eliminate distinct cell subsets. A significant focus will be set on the interplay of T-lymphocytes and myeloid leukocytes. The application of a recently developed spatial transcriptomics approach will allow us to examine cell-cell interaction in diseased valve tissue. In a translational approach using human tissue, we will assess cellular diversity and activation states by combining single-cell RNA sequencing and single-cell chromatin accessibility assays. The proposed experiments will help refine our understanding of inflammatory processes occurring during aortic valve degeneration and potentially open up new and precise therapeutic avenues.