Lysosomal-rich enterocytes (LREs) are a specialized population of enterocytes in posterior mid-intestine of zebrafish that exhibit high fluid-phase endocytosis activity and possess a large supranuclear lysosomal vacuole. These cells resemble premature enterocytes that are found in the ileum of pre-weaning mammals, which are distinct from mature enterocytes for their ability to efficiently uptake and process nutrients, particularly milk macromolecules. The importance of premature enterocytes in the utilization of nutrients during neonatal stage is reported through many studies; however, the cellular processes mediating protein absorption and digestion in these enterocytes remains poorly understood. My long-term goal is to understand the mechanism of protein uptake and utilization in these specialized intestinal enterocytes of neonatal mammals by studying an analogous population of enterocytes in zebrafish, LREs. A recent study from my lab has shown that the expression of the endosomal membrane protein Plasmolipin (Pllp) is enriched in LREs and that Pllp is critical for differentiation and endocytic function of LREs. Building upon our recent discovery of the crucial regulator of LRE function, I will explore the key cellular processes occurring in LREs. The use of zebrafish as a model system will be advantageous for this study because the optical transparency of zebrafish embryos will enable visualization of various cellular processes. Thus, using zebrafish as a model, I aim to uncover the endocytic pathways mediating protein internalization and trafficking in LREs (Aim1) and the regulators of lysosomal vacuole biogenesis and function in LREs (Aim2). The findings of the proposed study will elucidate the cellular processes mediating protein absorption and transport in LREs and provide a novel insight into the mechanism of lysosomal vacuole biogenesis and function in LREs. Additionally, our findings could ultimately contribute to the development of therapeutic strategies to reduce the incidence and severity of neonatal protein malnutrition.
Malnutrition is a significant global public health challenge and is attributed to approximately half of all child deaths in the developing world 1. Insufficient intake of dietary protein (i.e. protein malnutrition) is the most lethal form of malnutrition 2. Protein malnutrition during early postnatal stage is particularly harmful, resulting in stunted growth, reduced body weight, increased risk of infection, impaired brain development and function, and long-term dysfunction of metabolic and endocrine programs 3?7. This project will investigate the major cellular processes of the specialized population of intestinal cells responsible for protein absorption and digestion during neonatal stage. The ultimate goal of this project is to provide a foundational knowledge for the development of therapeutic strategies to reduce the incidence and severity of neonatal protein malnutrition. Thus, the proposed research is relevant to the part of the NIDDK's mission that seeks to support medical research and research training for digestive diseases and nutritional disorders to improve people?s health and quality of life.