Phone: 503 494-2997
Lab phone: 503 494-7149
Office: Room HRC 0426
Dr. Shi's Inner Ear Blood Flow Lab
Normal cochlear blood flow is critical for generating the endocochlear potential (EP) on which transduction in hair cells depends. Disruption of cochlear blood flow occurs in a wide variety of hearing disorders including loud sound-induced hearing loss (endothelial injury), ageing-related hearing loss (lost vascular density), and genetic hearing loss (Norrie disease: strial avascularization). Progression of blood flow pathology often parallels progression in hair cell loss and hearing impairment. To sustain hearing acuity, a healthy blood flow must be maintained. The blood supply not only provides energy to the organ, but is also a source of hormones and neurotrophic factors for maintaining organ health. A better understanding of the underlying mechanisms will facilitate the development of effective drug therapies for vascular dysfunction-related hearing loss. Hearing loss, accompanying with tinnitus and sound hypersensitivity, is a common condition which leads to communication problems and social isolation. The ultimate goal of Dr. Shi's research is to improve the quality of life of people with vascular dysfunction associated metabolic deafness. Under NIH grant support and In active collaboration with a number of groups both within OHRC and outside OHSU, Dr. Shi's lab has established a broad range of advanced techniques, including intra-vital microscopy for blood flow imaging in a living animal, systemic transplantation of bone marrow cells, a 'sandwich-pressure' method for isolating strial capillaries, a 'mini-chip' method for isolating and culturing BLB component cells, co-culture in 3D matrix gel, RNA-seq (RNA Sequencing), mass spectrometry, and siRNA transfection, and measurement of vascular permeability with multiple tracers, and advanced transmission electron microscopy. With these established research approaches, Dr. Shi's have progressively begun to gain a better understanding of how cochlear blood flow and the blood-labyrinth-barrier are regulated and discovered unique feature of stiral vascular system.
Research Projects in Dr. Shi's Lab
Inner Ear Blood Flow Regulation
The cochlea is a high energy demand organ which transduces acoustic input to electrical signals within a time scale of microseconds. The transduction critically depends on adequate vascular support to provide a sufficient supply of oxygen. Regulation of cochlear blood flow includes central neural and local and auto-regulatory pathways at the level of artery, arterioles and capillaries. Dr. Shi's lab particular focuses on myogenic properties of pericytes in the spiral ligaments in controlling capillary blood flow and maintaining microvascular homeostasis. The pericytes in the spiral ligament express contractile proteins, including α-smooth muscle actin and tropomyosin, and exhibit vasocontractility under both in vivo and in vitro conditions. The contractility of pericytes affects flow resistance of the vascular network, and alters overall blood flow. Pericytes may be also functionally linked to form a "pumping system" to regulate blood flow. A recent experiment from Dr. Shi's lab has demonstrated that cochlear blood flow is modulated by lateral fibrocyte input (Fig.1). Fibrocytes have long been regarded to facilitate generation of the endocochlear potential by recycling K+ from hair cell transduction, through gap junctions to strial intermediate cells and marginal cells, into the endolymph. Dr. Shi's lab discovered a novel that cochlear blood flow (CBF) is regulated by a fibro-vascular (type V fibrocyte-pericyte) coupled control mechanism signaled by both lactate, acting through monocarboxylate transporter 1, and nitric oxide, produced by neuronal nitric oxide synthase. The mechanisms underlying the pathophysiology of cochlear blood flow is of fundamental clinical importance. A better understanding of cochlear blood flow (CoBF) will enable more effective management of hearing disorders resulting from aberrant blood flow. Dr. Shi's laboratory is actively in the study of regional signals in control of cochlear blood flow and change of blood flow under various pathological conditions such as loud sound stimulation.
In the classic view, the BLB in the stria vascularis (strial BLB) is comprised of endothelial cells and an underlying basement membrane. Endothelial cells connect to each other by tight junctions and form a diffusion barrier which selectively excludes most blood-borne substances from entering the ear, protecting it from systemic influences. The Shi lab has shown the strial BLB is more complex. In addition to the microvascular endothelium, basement membrane, and pericytes, the strial BLB includes a substantial number of perivascular resident macrophages (PVMs). All together these cell types constitute a unique "cochlear vascular unit" (Fig.2). Signal communication between the cells may be critical for restricted permeability and transport, and for providing a proper environment for hearing function. Signaling between PCs and PVMs is essential for controlling the permeability of the BLB (Fig.3). The lab uses both in vivo and in vitro cell line based models to actively study cellular mechanisms controlling the permeability of strial BLB and changes in the BLB with aging, loud sound exposure, and inflammation.
Vascular Remodeling and Angiogenesis
Can damaged or degenerated vessels be regenerated in the ear? The Shi lab recently discovered a rich population of neural glial antigen 2 (NG2+)/vimentin+/nestin+ perivascular cells (mesenchymal stem cells) in the strial capillary network. Do these cells have angiogenic potential and serve as vascular progenitors? The question is timely since vascular injury, vascular density loss, and avascularization are seen in a wide variety of hearing disorders, including in loud sound-induced hearing loss, ageing-related hearing loss (lost vascular density), and genetic hearing loss (Norrie disease). Is restoration of cochlear blood flow critical for stabilizing or slowing hearing decline (e.g., presbycusis) and facilitating restoration of hearing function (e.g., loud sound-induced hearing loss)? To answer these questions, the Shi lab has created an in vivo pericyte depletion/vascular degeneration mouse model. With this model, in association with a newly established ex vivo tissue based-3D matrigel matrix model, the lab will investigate the relationship between vascular function, cell survival, endocochlear potential, and hearing. The lab will also determine the molecular signaling which initiates the angiogenesis in the stria vascularis needed for restoration of cochlear vascular function.
Fig.3 (A) &(B) Representative confocal and DIC images show new vessel grow and tip cell formation (arrowheads). The 3D matrigel models comprise isolated strial tissue explants of control and VEGF-A treated 4 week old C57BL/6 mice.