Andy Chang, Professor

Closed (1) Molecular mechanisms of oxygen sensing

Applications for fall 2021 are now closed for this project.

The ability to respond quickly to changes in oxygen availability is crucial for the survival of most animals. In mammals, a small chemosensory organ called the carotid body senses decreases in blood oxygen to increase breathing within seconds. While this important function has been known for over 90 years, the molecular mechanisms that mediate oxygen sensing in the carotid body are still unclear. Our lab discovered that an olfactory receptor activated by lactate mediates acute oxygen sensing by the carotid body. Thus, our current model is that lactate produced by metabolism in low oxygen activates this olfactory receptor to stimulate carotid body activity and breathing. This project is focused on taking a genetic approach in mice to define the interactions between this lactate receptor and other pathways in carotid body sensory signaling. Understanding the basic mechanism of oxygen sensing in the carotid body can have important implications in understanding adaptive responses of mammals to low oxygen conditions, such as high altitude, and increased oxygen demand in exercise and pregnancy. Furthermore, modulating carotid body activity may have therapeutic potential in stimulating breathing in people with depressed ventilation, such as during opiate overdose, and in improving symptoms of sleep apnea and chronic heart failure, diseases in which low oxygen conditions can be frequent.

An undergraduate researcher may participate at multiple levels of this project, including studying breathing patterns in whole animals and carotid body sensory signaling in primary cell and tissue culture. Depending on the specific project to be decided, techniques that can be learned include mouse genetics, whole body plethysmography, advanced microscopy (confocal, two photon imaging), tissue dissection, immunohistochemistry, and primary culture.

Qualifications: Students should have a background and interest in genetics, physiology, neuroscience, cell biology, or related field. It would be ideal for the student to have some bench work experience, but coursework is also acceptable.

Please note that students will commute to UCSF.

Weekly Hours: 12 or more hours

Off-Campus Research Site: University of California, San Francisco
Cardiovascular Research Institute
555 Mission Bay Blvd S
Room 384
San Francisco, CA 94158

Related website: http://andychanglab.ucsf.edu/

Closed (2) Identification of endogenous ligands for ectopic olfactory receptors

Applications for fall 2021 are now closed for this project.

Chemosensation is important for all organisms to detect and respond appropriately to changes in the external environment and internal state. Detection of volatile chemicals in the sense of smell is mediated by olfactory receptors (ORs) expressed in olfactory sensory neurons. ORs are G protein-coupled receptors that form the largest gene family in vertebrates. Since their discovery, expression of “ectopic” ORs outside the olfactory system has been seen in virtually all tissues. In all human tissues except the testis, only a small subset of ORs is expressed, and individual ORs are typically expressed in a limited number of tissues. Even for an OR that is expressed in many tissues, expression can be restricted to specialized cell types. This tissue and cell type- specific OR expression suggests that ectopic ORs may have functional roles outside the olfactory system.

For most ectopic ORs, no functional role has been described. However, there is growing evidence that ectopic ORs play diverse functional roles in sperm chemotaxis, myocyte migration, blood pressure regulation, renal glucose handling, and prostate cancer. Recently, we identified a mouse OR activated by lactate (Olfr78) that mediates acute oxygen sensing by the carotid body, a chemosensory organ that senses decreases in blood oxygen to stimulate breathing.

This project aims to identify other ectopic ORs and screen for bioactive molecules that may stimulate them in a heterologous system. Our hypothesis is that ectopic ORs will be activated by ligands produced by the body. Defining new ligand-OR pairs can lead to the discovery of new sensory functions of known cell types and identification of novel sensory cell types that monitor the internal state. We are actively screening for new small molecule regulators of ORs to test for activity in vivo.

Qualifications: This project will involve molecular biology and biochemistry in cell culture and could extend to a small molecule drug screen. Students should have a background and interest in molecular biology, biochemistry, cell biology, or related field. Some hand-on experience with cell culture would be beneficial.

Please note that students will commute to UCSF.

Weekly Hours: 12 or more hours

Off-Campus Research Site: University of California, San Francisco
Cardiovascular Research Institute
555 Mission Bay Blvd S
Room 384
San Francisco, CA 94158

Related website: http://andychanglab.ucsf.edu/