Grant: Discovery Grants Program - Individual

Long term vision: My research program centers around the identification and characterization of fundamental molecular participants that regulate brain function. Overview: The central nervous system (CNS) is immersed in the cerebrospinal fluid (CSF) produced by the epithelial cells of the choroid plexus (CP). In addition to the production of CSF, CP also actively synthesize and secrete diverse signaling molecules that influence critical brain functions including neurogenesis and energy homeostasis. Ion channel activation is essential to the secretory functions of CP as they transport the integral elements required for the synthesis of the CP secretome. Calcium entry and signaling is thus, a crucial component of this mechanism but remarkably, the regulators of this process remain largely undetermined. We have detected strong presence of Transient Receptor Potential Vanilloid-type 4 (TRPV4), nonselective, calcium permeant, cation channel in the CP and have observed its ability to robustly influence calcium signaling in the cells of the CP. Short term objectives: We hypothesize that TRPV4 is a master regulator of CP functions. Through the three research aims, we will: Aim 1: Establish the presence of TRPV4 in the healthy brain. Utilizing a novel transgenic reporter TRPV4 mice and immunohistochemistry we will confirm the robust expression of TRPV4 observed in our preliminary experiments, in both male and female animals. Aim 2: Determine the role of TRPV4 in regulating CP secretome in the healthy brain. After pharmacological modulation of TRPV4 in the CP, we will define its role in calcium signaling and secretome composition in the healthy brain. Aim 3: Ascertain the age-related changes in CP functions in the healthy brain. By using young and aged, otherwise healthy mice we will investigate the impact of aging in TRPV4 and CP functions and its influence on the maintenance of brain homeostasis in the aged brain. HQP training: The proposed aims have considered all aspects of HQP training, including the development of strong intellectual, analytical and research skills. The experiments outlined in the proposal are designed to promote their interest in ion-channel biology and brain physiology and will also provide advanced training in molecular biological techniques, cellular imaging and animal experiments, enabling their transition into diverse scientific careers. Significance: Even though the contribution of CP to brain homeostasis is well recognized, the molecular machinery that drives its complex functions are surprisingly unexplored. The proposed studies will advance fundamental knowledge on the multifaceted roles of the choroid plexus and will provide new perceptions on homeostasis and healthy aging in the CNS. On a broader point of view, our investigative insights will impact on our understanding of how multiple brain cell types interact and contribute to the collective regulation of brain functions.