Calcium Homeostasis in Health and Disease

Calcium ARC is a unique interdisciplinary collaborative environment of more than 25 investigators from 18 laboratories in 15 Sections/Departments from BUSM and Charles River BU campuses. These investigators are experts in complementary fields, who share common interest in Ca²⁺ homeostasis and are seeking an opportunity to work together on common projects directly related to various diseases. Calcium ARC will allow us to look at the mechanisms of cellular function from many different perspectives, will promote development of novel ideas, enable us to identify common molecular determinants and mechanisms of Ca²⁺ signaling in diverse cell types, and allow their translation to human disease. As a group, Calcium ARC will have new synergistic power to address the mechanisms of impairment in ER/SR Ca²⁺ homeostasis and its pathological consequences for cardiovascular, skeletal, pancreatic and other systems, and relate them to human disease. Calcium ARC supports fruitful collaboration between active investigators, and helps in creation of new advanced knowledge.

Specific Goals:

• To create a new collaborative environment and multidisciplinary integrative approach (from single molecules to the disease of interest) that will become a new source of ideas and interdisciplinary knowledge in the specific area of Ca²⁺ signaling and translational studies in health and disease
• To share conceptual and experimental expertise, and to create additional valuable resources to successfully address the questions of common interest
• To open new directions for interdisciplinary research, and bring new possibilities for collaborative grant applications for extramural funding
• To provide an important platform for multidisciplinary education for Calcium ARC members to enrich their intellectual and experimental potential through regular seminars (with inside and outside speakers), training sessions, and discussion panels

ANNOUNCEMENTS:

Guest speaker for our ARC meeting:
Thursday, June 14th, 2012
2:00- 3:30pm, X-715
Fumihiko Urano, MD, PhD Department of Medicine, Washington University School of Medicine, St. Louis
will present a seminar: “Human Endoplasmic Reticulum Disease: From Causality to Cure”

Participating Faculty

Scientific background:

Ca²⁺ signaling affects every aspect of a cell’s life and death, and impairment of the dynamic equilibrium of Ca²⁺ between cytosol and endoplasmic /sarcoplasmic reticulum (ER/SR) is one of the leading causes of cellular dysfunction in a wide variety of pathological conditions. Failure of ER/SR to sustain its Ca²⁺ content (which is essential for protein folding and other vital cellular processes) results in Ca²⁺ store depletion that is known to be one of the major elements of a complex, but poorly-defined pathological phenomenon known as ER stress. Significant progress has been achieved in identification of specific molecules and signaling cascades that are involved in ER/SR Ca²⁺ homeostasis, but very little is known about the causes and consequences of their malfunctioning and their role in human disease.

Focus Groups:

Cardiovascular Group: Will focus on molecular mechanisms of ER/SR Ca²⁺ store depletion and test/establish their role in endothelial cells, cardiac myocytes and vascular SMC with a focus on cardiovascular dysfunction and diabetic retinopathy. Using complimentary expertise of R.Cohen (SERCA, endothelial and SMC, complications of diabetes, angiogenesis), V.Bolotina (vascular SMC, iPLA₂β, Ca²⁺ signaling), W.Colucci (cardiac myocytes, cardiac hypertrophy, role of SERCA and Ca²⁺), M.Trojanowska (endothelial cells, ER stress), S.Roy (endothelial cells, angiogenesis, retinopathy), M.Kirber (SMC, Ca²⁺ signaling, imaging), we plan to test the mechanisms and cardiovascular consequences of impaired SERCA-dependent store refilling, and/or STIM1/iPLA₂β-dependent Ca²⁺ entry. We will focus on the studies of ER/SR Ca²⁺ homeostasis in the cells and cardiovascular problems (heart hypertrophy, vascular dysfunction, and potential retinopathy) of two new mouse models (SERCA cysteine to serine-674 knock-in mice, and inducible iPLA₂β ^ex2 KO mice) that are available in the labs of R.Cohen and V.Bolotina. Preliminary studies showed that these mice have different forms of cardiovascular dysfunction, which we want to study in detail. To distinguish between cardiac and vascular phenotypes in these mice, we plan to develop a new inducible vascular SMC-specific iPLA₂β ^ex2 KO mouse model. To identify the translational value of our findings, we plan to obtain the relevant human tissue samples (through NDRI) from healthy individuals and those with cardiovascular disease and/or diabetes, and characterize the differences in expression and function of the molecules of our interest.

Skeletal Muscle Group: will focus on the mechanism and molecular determinants of ER/SR Ca²⁺ store depletion and their role in skeletal muscle dysfunction. Using complimentary expertise and interests of S.Girgenrath (skeletal muscle, dystrophy, regeneration, ER stress), M.Montano (skeletal muscle, aging), I.Dominguez (skeletal muscle), V.Bolotina (Ca²⁺ signaling, STIM1, iPLA₂β), M.Kirber (Ca²⁺ release channels, imaging) we will focus on determining the specific components of ER/SR Ca²⁺ homeostasis that can be impaired in (and/or lead to) congenital and other forms of muscular dystrophy. We will also test if regeneration of skeletal muscle may be impaired in SERCA cysteine-674 knock-in mice and inducible iPLA₂β ^ex2 KO mice.

Diabetes Group: is interested in the role of ER Ca²⁺ homeostasis in insulin secretion and mitochondrial function in beta cells with a focus on diabetes. Synergistic expertise and interests of B.Corkey (Ca²⁺, metabolism, beta cells, diabetes), J.Deeney (metabolic control of insulin secretion, beta cells), V. Bolotina (Ca²⁺ signaling, ion channels, membrane potential, iPLA₂β), O.Shirihai (mitochondrial dynamics, beta cells, imaging), A.Molina (fission/fusion, beta cells) will allow us to test some new ideas about a) the role of ER-related Ca²⁺ signaling in insulin secretion, b) crosstalk of ER and mitochondria and its role in fusion/fission, and c) potential role of iPLA₂β and Ca²⁺ signaling in iron-related beta cell deficiency. For some of these studies, we may need to develop new β cell specific iPLA₂β ^ex2 KO mice.

Additional collaborative projects: Calcium preARC resulted in generation of multiple new ideas that have potential to grow into additional focus groups. The Calcium ARC will support and provide a strong platform for development of these newly emerging projects:

• The effects of disease-related mutations of human iPLA₂β on its tertiary structure and function

(Y.Xia,  G.Rymarczyk, V.Bolotina),

• The role of Ca²⁺ signaling in the establishment of cell fate and patterning of the embryonic lung

(W.Cardoso, V.Bolotina).

• The role of CaMKII / iPLA₂β interaction in vascular smooth muscle function

(K.Morgan, M.Kirber, V.Bolotina),

• The role of PKC-dependent regulation of Ca²⁺ release on phenoptypic changes in vascular SMC

(M.Kirber, V.Bolotina),

• Identification of new Ca²⁺ signaling targets of oxidative stress and mito-protective role of new SOD/catalase mimetics (S.Doctrow, V.Bolotina),

Calcium ARC as a new resource:

The Calcium ARC will become a new resource for all the investigators interested in Ca²⁺ homeostasis in health and disease. A new Calcium ARC Core will be created to help achieve scientific goals, and promote new discoveries that will lead to translation of basic cellular mechanisms to human disease. This ARC core will include the following advanced resources that otherwise may not be available for ARC members:

• Advanced Ca²⁺ imaging with methodological seminars, hands on training, and the use of Imaging Core facility, partially covered by the ARC funds
• A bank of molecular tools (vectors, siRNAs, TaqMan assays) has been created and will be freely available for all ARC members to enable expression of fluorescently tagged and/or genetically engineered proteins, down-regulation of target proteins, and profiling of gene expression in animal and human tissues and cell lines. With ARC funds this bank will be expanded by additional Ca²⁺-sensitive probes and Ca²⁺-sensing proteins directed to specific cellular compartments, and by other advanced molecular tools
• Existing knock-out and knock-in animals will be shared, and new models will be created using ARC funds to assess the role of targeted genes/proteins in the development of different diseases. Collaborative efforts and multidisciplinary expertise of ARC members will enable the most complete studies and characterization of such animals.
• Samples of normal and diseased human tissue will be obtained through NDRI, shared, and collectively studied by ARC members.         

Plans for frequency of meetings

We plan to have 1-2 meetings per month, which will include:

• research seminars (3 external and 4 internal speakers/year),
• work-in-progress group meetings (3-4/year to present research findings and discuss/evaluate the progress of each project),
• methodological seminars (2/year) and training sessions (as needed),
• Symposium (1/year) that will include external expert speakers, speakers chosen from ARC, short talks by the ARC trainees and students, and a poster session.
• Each focus group will add meetings as needed.