Research

Ciliary gates and ciliopathies

Unlike other cellular organelles, the ciliary lumen is open to cytoplasm. Mounting evidence suggests that gating mechanisms regulate the selective ciliary entry of membrane and soluble proteins, whose coordinated function makes the cilium a distinct functional entity.

Most known ciliopathy proteins localize to cilia basal structures but not cilia proper. This hints at the importance of cilia gating.

Dr. Hu's team is one of the first labs to show that transition fibers — the poorly characterized cilia basal structures — are a critical part of the ciliary gate to regulate the ciliary import of both membrane and soluble proteins. Disrupted cilia gating leads to defective ciliogenesis, cilia signaling, and human and mouse ciliopathies. Dr. Hu's team is studying the role of transition fibers in the context of cilia function and pathogenesis ARLs in ciliopathies. The team aims to devise means to modulate cilia function by adjusting the gating.

Cellular switches in ciliopathies

Small GTPases function as molecular switches in diverse membrane- and cytoskeleton-related cellular processes, alternating between inactive GDP- and active GTP-bound states. Small GTPases are switched on by guanine nucleotide exchange factors (GEFs) and off by GTPase activating proteins (GAPs).

The unique features of small GTPases have made them and their effectors favorable therapeutic targets in many human diseases. The family of mammalian ARF and ARL GTPases includes 29 members, but the in vivo roles and regulators (GEF, GAP and effectors) of most ARFs or ARLs are poorly defined.

A comparative genomics study revealed that Arl3 and Arl6 are present only in ciliated organisms. Mutations in ARL3 or ARL13B cause the classical form of Joubert's syndrome. Arl3-/- and Arl13b-/- mice exhibit typical ciliopathy manifestations. Human ARL6 has been identified as BBS3, one of the loci involved in the ciliopathy Bardet-Biedl syndrome. This suggests that the ciliary ARLs play decisive roles in the context of cilia.

Dr. Hu's research team aims to determine the function and regulators of the ARLs, with the ultimate goal to identify novel and actionable therapeutic targets to prevent, delay or halt ciliopathy progression.

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases. It is caused mainly by mutations in PKD1 and PKD2, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively.

Although the molecular mechanism of cystogenesis in PKD is still controversial, accumulating evidence in human genetics and hypomorphic rodent models suggests that the severity of the disease closely correlates with a decreasing dosage of functional polycystins. Proper targeting and maintenance of polycystins on the cilia surface are critical for cilia as mechanosensors.

Theoretically, restoring the functional level of ciliary polycystins is a promising therapeutic strategy to delay or even prevent cystogenesis. However, a lack of knowledge of how the ciliary targeting and maintenance of polycystins are controlled impedes the exploration of this strategy. Dr. Hu's team focuses on understanding the ciliary trafficking of polycystins and identifying druggable targets to be used in PKD therapeutics.

Cilia and metabolic disorders

Obesity and the associated type 2 diabetes mellitus are major public health issues. It is accepted that the development of obesity stems from the interaction of environmental factors with genetic factors.

Although monogenic genetic obesities are rare, the elucidation of the physiological function of causal genes, such as the identification of leptin in ob/ob mutant mice, was transformative in understanding obesity physiopathology. Cilia-related disorders, also known as ciliopathies, are a significant part of genetic obesities, such as Bardet-Biedel syndrome and Alstrom syndrome, highlighting the important role of ciliary signaling in the pathogenesis of obesity.

Primary cilia present on most cell surfaces in the human body and are like cellular "antennas" used by cells to sense the environment ranging from mechanical and chemical cues to temperature or osmolarity. Cilia dysfunctions contribute to a wide spectrum of human syndromic diseases. However, major gaps exist in understanding the molecular mechanism behind cilia dysfunction-associated manifestations.

Based on initial discoveries made in unique ciliopathy rodent models, Dr. Hu is collaborating with a highly complementary team to investigate the unexpected but central role primary cilia play in adipogenesis of both white and brown fat tissues, and the implications for human metabolic disorders.