Thursday, April 18, 2024
4/18/2024
¿ DESCRIPTION (provided by applicant): The cilium is a small cellular organelle which broadly exists throughout the human body in either motile or immotile form. Motile cilia generate force by beating for directional fluid movement, whereas primary (immotile) cilia are involved in sensory processes and cellular signaling. Defects of cilia structure, including cilia length, and function result in a wide range of human disease symptoms referred to as ciliopathies and affect most of organs, including kidney, brain, limb, eye, ear, liver and bone. Phenotypes related with ciliopathies are classified two categories, motile or immotile cilia related disorders. Motile cili disruption causes improper establishment of left-right (LR) asymmetry, hydrocephalus in brain and respiratory tract infections. Sensory and signaling disorders in primary cilia cause retinal degeneration in the eye, anosmia in olfactory epithelium, kidney cyst formation and obesity. Although ciliopathies have been associated with mutations in over 40 genes to date, the pathogenesis of most ciliopathies still remains to be discovered. To understand the pathogenesis of ciliopathies, we will explore the molecular mechanism that control cilia assembly. We recently found that blocking the Smad2/3-dependent TGF-ß pathway in Xenopus embryos shortened motile cilia in several tissues. This is the first report about the role of TGF- signaling in cilia formation. We further found that a molecular network activated by TGF-ß signaling is independent of the function of a major ciliogenesis regulator FOXJ1. Thus, we hypothesize that the TGF-ß/Smad2 pathway activates a new molecular network to regulate cilia length. To identify genes in the TGF-ß-dependent cascade, we used RNA-seq to compare transcriptome profiles of control ciliated tissues and ciliated tissues with blocked TGF-ß signaling. Blocking TGF-ß signaling reduced the expression of two ciliary genes that have been reported to alter cilia length as well as 12 transcription activators (TAs). To investigate the TGF ß-dependent network that regulates cilia length, we propose the two aims. In the first aim, we will elucidate the TGF-ß-dependent molecular network that regulates cilia length. In the second aim, we will uncover the TGF-ß-dependent mechanism that regulates cilia length. Our studies will provide new insights into our understanding of cilia length regulation and will contribute to revealing the molecular mechanism of human ciliopathies with unknown etiology by identifying new factor(s) that regulate cilia formation.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
