Javid Moslehi, MD
An overarching theme of the Moslehi laboratory is to better understand cardiovascular signaling, especially in response to various stressors including inflammation, aging, and hypoxia. The Moslehi laboratory is closely integrated with the newly formed Section of Cardio-Oncology and Immunology at UCSF, leveraging novel clinical observations into fundamental basic questions that can be dissected in the laboratory, with the hope that laboratory discoveries translate into innovations in diagnostics and therapeutics for our patients. Using “cardio-oncology” as a platform, the Moslehi laboratory has previously defined novel human disease syndromes with subsequent basic laboratory findings translating to novel treatments for patients.
Cardio-Immunology
A major focus of the Moslehi Laboratory has been fundamental interactions between the cardiovascular and immune systems. We are also utilizing recent advancements in immuno-oncology to better treat human cardiovascular disease. Our group’s interest in cardio-immunology came about after we defined new cardiovascular clinical syndromes associated with of cancer immunotherapies, especially in the context of immune checkpoint inhibitor (ICI). We have described ICI-associated myocarditis (Johnson et al, NEJM, 2016; Moslehi et al, Lancet, 2018) and other ICI-associated cardiovascular toxicities (e.g., pericarditis, vasculitis, and arrhythmias) (Salem et al, Lancet Oncology. 2018). We have utilized our expertise as myocyte and mouse biologists to generate several pre-clinical models of ICI-associated myocarditis (Wei et al, Cancer Discovery, 2021). These models suggest a fundamental role for immune checkpoints (for example, CTLA-4 and PD-1) in cardiovascular homeostasis and myocardial diseases. Using novel single cell platforms and spatial transcriptomics, we are currently elucidating specific immune populations that mediate ICI-myocarditis. In addition, we are defining novel cardiac mechanisms that maintain immune tolerance in the heart. With respect to ICI-myocarditis, we have already developed case definitions (Bonaca et al. Circulation, 2019) as well as better diagnostic and therapeutic strategies for our patients (Salem et al. NEJM, 2019). More fundamentally, we have been interested in the roles that immune checkpoints play in the heart and vasculature.
At UCSF, we have additionally built a new center for cardio-immunology, specifically focusing on cardiac and vascular disease pathologies where immune system plays a role. A novel area of focus for the Moslehi laboratory at UCSF will be utilizing genomics and genome engineering technologies to better understand cardiovascular-immune interactions and to harness reprogrammed immune cells to treat cardiovascular diseases.
Kinase Signaling in the Heart
Kinase inhibitors used in oncology have been transformative in cancer treatment but can lead to cardiovascular sequelae. We believe that the cardiovascular sequalae of these novel “targeted” cancer therapies can provide fundamental insights into human cardiovascular biology and can potentially inform cardiac drug discovery.
Hypoxia, HIF, VEGF Inhibitors, and the Heart
The 2019 Nobel prize in physiology and medicine was awarded to three scientists who helped define the the cellular sensing of oxygen levels and regulation of physiologic hypoxia (Moslehi et al, JCI, 2019). This oxygen-sensing mechanism involves the tumor-suppressor protein VHL, which is mutated in many kidney cancers, and proteins known as hypoxia inducible factors, HIF-1α and HIF-2α, which induce angiogenesis to inducing transcription of Vascular Endothelial Growth Factor (VEGF) and other angiogenic factors. We have been interested delineating the fundamental roles that this pathway plays in cardiovascular signaling and have shown EglN/HIF to play critical roles ischemic protection and cardiomyopathy.
