TRP channels as fundamental sensors of the cerebral microcirculation

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PROJECT SUMMARY Optimal flow of blood within the brain is ensured by two processes: (1) autoregulation, a collection of intrinsic mechanisms that continuously adjust the microcirculation to maintain a constant flow of blood in the face of changes in perfusion pressure, and (2) neurovascular coupling, an ensemble of cerebral vasculature physiological processes that tightly match local blood flow to the needs of metabolically active regions of the brain. These distinctive responses are necessary for brain health and function but remain incompletely understood. Further, loss of microvascular control is associated with common age-related cerebrovascular pathologies, including stroke, cerebral small vessel diseases (cSVDs), and vascular cognitive impairment and dementia (VCID). The overarching goal of this proposal is to address this critical knowledge gap by providing a better understand of how the brain’s ever-changing milieu of physical, environmental, endocrine, paracrine, metabolic, and neurochemical stimuli are sensed by the cerebral microvasculature at the cellular level, and how these signals are processed to ensure homeostasis and adaptability. The primary mechanistic focus of our research is ion channels of the transient receptor potential (TRP) family—polymodal sensors of many types of physical and chemical stimuli present in all cells. Over the past 10 years, our research team has discovered that TRPM4 (TRP melastatin 4) and TRPML1 (TRP mucolipin 1) channels in cerebral vascular smooth muscle cells are important for the development of myogenic tone, a fundamental autoregulatory mechanism, and has demonstrated critical sensory roles for TRPA1 (TRP ankyrin 1) and TRPV3 (TRP vanilloid 3) channels on the endothelium of cerebral arteries and arterioles. Continuing with this theme and using advanced biomedical imaging approaches and next-generation genetic mouse models, we will weave together the central concepts established by our independent projects to develop a comprehensive overview of TRP channels as cellular sensors in the cerebral microvasculature. Examples of proposed studies include investigations that will define the nanoscale architecture of TRP channel signaling networks in health and disease using superresolution microscopy, elucidate how TRPML1 channels are endogenously regulated in smooth muscle cells to prevent vascular hypercontractility during myogenic vasoconstriction, and test the hypothesis that TRPA1 channels on brain capillary endothelial cells act as detectors of reactive oxygen species to promote neurovascular coupling. We will layer basic science investigations intended to elucidate fundamental regulatory mechanisms with research designed to understand how processes controlled by TRP channels go wrong and contribute to the transformation of healthy small vessels in the brain to a disease state during aging. To further this goal, we are developing and characterizing new genetic models of age-related cSVDs and VCID in collaboration with investigators at UCSF, and propose to use this unique resource to explore themes that include the involvement of TRPM4, TRPML1, and TRPA1 channels in cerebral vascular dysfunction during age-related cSVDs and VCID.