# The STIM/Orai interface and novel tools to control vascular smooth muscle phenotype > **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $32,209 ## Abstract PROJECT ABSTRACT Vascular smooth muscle cells (VSMCs) are crucial in maintaining the integrity of vessel walls, vascular tone, and contraction. They have the amazing potential to dedifferentiate upon mechanical injury or inflammation from a quiescent state to a proliferative (synthetic) state. This high degree of VSMC plasticity is crucial in wound response and healing, but also predisposes the cell to adverse formation of neointima near the vascular lumen. Neointimal formation tightens the arterial wall, restricting blood flow and is the pathogenic base for occlusive cardiovascular diseases such as atherosclerosis, restenosis, and systemic hypertension. Therapies to address neointimal formation are scarce and non-selective. Understanding and targeting mechanisms utilized by synthetic VSMCs is of upmost clinical importance. What has been observed in the transition between quiescent and synthetic VSMCs, is a phenotypic modulation of proteins involved in calcium signaling. Calcium is a vital second messenger involved in nearly every cellular process from proliferation to apoptosis. As VSMCs change from their contractile quiescent state to a proliferative state, they rely less on voltage-gated calcium channels and depend more on the Orai1 calcium channel. Orai1 is essential in the calcium homeostatic process known as store operated calcium entry (SOCE). Calcium stores within the endoplasmic reticulum (ER) are sensed by a family of proteins known as STIM. Upon store depletion, STIM proteins oligomerize, undergo conformational change, and migrate from ER to ER-plasma membrane (PM) junctions. Unfolding of the STIM reveals a powerful interacting site known as the STIM-Orai activating region (SOAR), which is able to bind and activate the highly calcium selective PM Orai channels. Elucidation and exploitation of the STIM-Orai binding interface presents an exciting new therapeutic avenue for cardiovascular disease. How Orai couples with STIM is a topic under much speculation. Previous studies propose that either two Orai cytosolic regions are involved, known as the N-terminus and transmembrane extension (TM4ext), or that adjacent TM4exts are required to form a dimerized binding pocket. In order to solve the mystery of the STIM- Orai coupling interface, I developed a novel set of PM tethering peptides that can exclusively interrogate the TM4ext of any of the three major mammalian Orai subtypes, Orai1-3. My recent work presents an exciting new paradigm for STIM-Orai interacting, that the TM4ext is necessary and sufficient in acting as a sole binding region. Furthermore, I found out that the Orai3 TM4ext ahs tremendous binding interaction with STIM over the more ubiquitous Orai1. This F31 proposal builds upon these exciting developments and represents a huge integral part for the training of James Baraniak. Continual work on this proposal will interrogate how STIM-Orai interacts using these novel peptides, and how they may be used as a powerful tool in co... ## Key facts - **NIH application ID:** 9992168 - **Project number:** 1F31HL152619-01 - **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR - **Principal Investigator:** James Henry Baraniak - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $32,209 - **Award type:** 1 - **Project period:** 2020-06-01 → 2022-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9992168 ## Citation > US National Institutes of Health, RePORTER application 9992168, The STIM/Orai interface and novel tools to control vascular smooth muscle phenotype (1F31HL152619-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9992168. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*