Zhi Zhou, PhD | School of Life Science and Technology, Shanghaitech University; Zhiwen Deng, PostDoc; Songzhou Jiang, RN; Xiaoyang Chen, PhD; Houkun Lv, PhD; Jiajun Zheng, PhD; Kunkun Yu, MS; Qianshun Yao, MS; Yueyue Liu, MS
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2024
The aging population, coupled with increasing concerns regarding testicular aging and hypogonadism, has led to growing prevalence of male infertility and endocrine disorders that significantly affect quality of life. Currently, the only available treatment is testosterone replacement therapy (TRT), which is associated with various side effects, including testicular atrophy, impaired spermatogenesis, and an increased risk of all-cause mortality rate.
To better understand the underlying mechanisms of testicular aging and develop alternative therapeutic strategies, our team previously established a comprehensive single-cell atlas of the human testis across the lifespan. Using both cellular and animal models, preliminary research revealed that abnormal lysosomal acidification in Sertoli cells is a key factor contributing to accelerated testicular aging. Furthermore, targeting lysosomal ion channels with ML-SA1 to restore proper lysosomal acidification demonstrated the ability to repair Sertoli cell function and alleviate the pathological effects of testicular aging. The precise mechanisms driving lysosomal acidification abnormalities during testicular aging remain unclear. Moreover, ML-SA1, despite its promising effects, has limitations related to its poor druggability.
This project aims to further elucidate the mechanisms by which testicular aging disrupts lysosomal acidification and to identify one or two critical therapeutic targets that can be leveraged for treating testicular aging. In addition, the small molecule compounds will be screened to restore lysosomal acidification and mitigate the pathophysiological consequences of testicular aging.