Targeting the Calcitonin-BMP1 Pathway in Atrial Cardiofibroblasts to Ameliorate Atrial Fibrillation

最普遍的疾病之一是心房颤动（AF），每年至少造成18万人死亡

One of the most prevalent diseases is atrial fibrillation (AF), which contributes to at least 180,000 deaths annually and is expected to affect twelve million people in the U.S. by 2030. Excessive atrial fibrosis increases resistance to therapy and decreases AF-free survival in AF patients by creating a substrate for atrial reentrant arrhythmias. Increased interstitial fibrosis is caused by dysfunctional atrial cardio-fibroblasts (ACFs) that secrete excessive collagen into the extracellular matrix. However, detailed molecular mechanisms of the signaling pathways regulating ACFs are yet to be uncovered, which could enable the development of a novel treatment for AF. The Wehrens Lab in collaboration with Dr. Reilly (Univ. of Oxford) has recently identified calcitonin (CT) as a paracrine signaling molecule that is released from cardiomyocytes and suppresses atrial fibrosis. The study showed that CT overexpression ameliorates AF progression in a novel murine model of spontaneous AF. Moreover, it found that treating human cultured ACFs with CT inhibited BMP1 cleavage activity and reduced collagen deposition. BMP1 is a zinc-dependent protease that cleaves and activates several profibrotic substrates, including the TGF- β large latent complex (LLC) to release secreted TGF-β, a profibrotic signal protein. However, the roles of BMP1 that are regulated by CT have yet to determined. While the previous study suggests that CT treatment ameliorates AF development in mice, it also found that ACFs from AF patients are resistant to CT treatment because the CT receptor (CTR) is downregulated as AF progresses. The hypothesis is that a reduction in CT receptor activation on ACFs leads to enhancement of BMP1 activity, more TGF-β LLC cleavage, and thus more atrial fibrosis and AF progression. To test this hypothesis, Aim 1 will determine whether BMP1 activity mediates the regulation of TGF-β by CT in human ACFs, and Aim 2 will determine whether Bmp1 knockout protects against the development of atrial fibrosis and AF in mice. These studies will provide a more detailed understanding of the signaling pathway downstream of CT in atrial fibrosis and AF and offer a candidate for a novel gene therapy approach to reduce atrial fibrosis for the treatment of AF. To accomplish these goals, the proposed training plan includes learning the relevant research skills such as optical mapping, telemetry ECG recording and analysis, and histology for analyzing fibrosis. An additional aspect of the training plan involves shadowing cardiologists throughout the Texas Medical Center as they care for patients with AF and other arrhythmias and practicing clinical skills during graduate school at the San José Clinic. The research environment is likewise well suited to the project and training goals and includes dedicated lab spaces for molecular biology studies, mouse electrophysiology and telemetry recording, mouse surgery, and optical mapping as well as a mentor and postdoctoral associates who are committed to ensuring the project is successful. In addition to helping to achieve the proposed research goals, the training plan and environment will also enable career goals of becoming a physician-scientist and integrating basic science research with patient care to be achieved.