Akiko Hata, PhD

Professor
Cardiovascular Research Institute
+1 415 476-9758

Research in my lab focuses on the role of the BMP/TGFb signaling pathway in the maintenance of vascular homeostasis, control of vascular remodeling, and pathogenesis of vascular proliferative diseases, including idiopathic pulmonary arterial hypertension (IPAH), restenosis, and atherosclerosis. Our long-term objective is to understand the molecular pathogenesis of vascular proliferative diseases as a result of deregulation of the signaling pathways which are critical for a control of vascular smooth muscle cells (vSMCs) phenotype and vascular remodeling. We are currently focusing on following three projects.

#1: To understand the mechanism of regulation of miRNA biosynthesis by Smad proteins. We are investigating the mechanism of regulation of miRNA biosynthesis by TGFbs and BMPs, a process crucial to a more general understanding of the TGFb/BMP-mediated phenotype switch underlying the pathogenesis of IPAH. We completed miRNA microarray analysis and identified about 20 novel miRNAs that are regulated by TGFbs and BMPs at the Drosha processing step similarly to miR-21 in PASMCs. Comparison of these miRNA sequences exhibited a highly conserved RNA sequence element within the stem region of pre-miRNAs, suggesting possible mechanism that Smads directly recognize and associate with the RNA sequence element to selectively regulate a specific set of miRNAs. We will study a role of Smad in the Drosha microprocessing enzyme complex by testing a possibility that Smad promotes conformational change in the stem of the pre-miRNA and facilitate a cleavage reaction by Drosha. We will investigate the structural determinants by which a subset of miRNAs is recognized by Smads by investigating a structure of Smad proteins associated with pre-miRNA stem region. We will also investigate a role of RNA helicases, cofactors of Smad proteins in the Drosha complex. We will investigate a role of different DDX family of RNA helicases that interact with Smad proteins in the Drosha complex.

#2: To examine a role of miRNAs in the regulation of vSMC phenotype. We are exploring the potential in vivo role of miRNAs regulated by BMP or PDGF pathway in the vascular remodeling in response to vascular injury, such as angioplasty. To determine the potential role of miR-24 in neointimal lesion formation after angioplasty, a fluorescent-dye labeled anti-miRNA or miRNA mimic will be delivered locally to the injured carotid artery using a polymer as a vehicle. To study molecular mechanism of modulation of vSMC phenotype by miRNAs, we will identify targets of specific miRNA in vSMCs. We are performing a novel biochemical technique to identify targets of a specific miRNA. We completed the identification of miR-21 targets in PASMCs. Potential targets will be validated by examining the effect of miRNA on the 3’-UTR sequence of potential target genes, and functional significance of target gene products in the regulation of vSMC genes by the BMP or PDGF signaling pathway.

#3: To understand an expression of miRNAs in peripheral blood in patients with cardiovascular diseases. It has been reported that miRNAs can be exported from cells in an exosome-dependent manner, stabilized, and hence detected in peripheral blood. More interestingly, serum or plasma samples from cancer patients exhibit a specific miRNA expression pattern different from serum samples from healthy individuals, suggesting that miRNA expression in peripheral blood might serves as a molecular signature of human disease and could be used as a diagnostic marker. We recently completed a miRNA microarray study using serum samples from hypertrophic cardiomyopathy (HCM) patients, heart failure patients without HCM, and patients with acute myocardial infarction compared with serum samples from normal individuals. Interestingly, patients with these cardiovascular conditions exhibit an elevation or reduction of a specific set of miRNAs in comparison with normal samples, which raises a possibility that some of those regulated miRNAs can be used to define specific pathological conditions and save as biomarkers of these conditions. We plan to investigate the mechanism of regulation of miRNA expression in peripheral blood.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Vascular & Cardiac Biology
Research Summary: 
TGFbeta family of signaling pathway
Publications: 

Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106.

eLife

Celona B, von Dollen J, Vatsavayai SC, Kashima R, Johnson JR, Tang AA, Hata A, Miller BL, Huang EJ, Krogan NJ, Seeley WW, Black BL

TGF-ß Signaling from Receptors to Smads.

Cold Spring Harbor perspectives in biology

Hata A, Chen YG

Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome.

Science signaling

Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A

Dysregulation of microRNA biogenesis machinery in cancer.

Critical reviews in biochemistry and molecular biology

Hata A, Kashima R