American Heart Association (AHA)

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Limiting Language
An institution may submit only one Center (and related Projects) application in response to this RFP.

Purpose
The intent of this initiative is to support a collaborative network of researchers whose collective efforts will lead to enhanced understanding of the earlier detection and/or delaying progression of valvular heart disease. Therefore, this Request for Proposals seeks applications that can address these critical questions and stimulate significant advances in these areas of valvular heart disease. All proposed projects must address valvular heart disease. Within that context and as presented above, an array of potential areas of investigation exists. Both human studies and appropriately designed animal models that can foster understanding of valvular heart disease may be proposed. 

STUDY POPULATION(S)

• For studies involving human subjects, researchers must ensure that participant populations accurately reflect those affected by the disease under investigation. Efforts should be made to include individuals whose health criteria align with the prevalence and impact of the disease, thereby enhancing the relevance and applicability of the study findings.
  
   
• Important: Applicants should design studies that incorporate both realistic recruitment goals and sufficient statistical power to ensure valid results.

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An institution may submit only one Partner Hub (and related Projects) proposal or one Community Engagement Resource Center proposal. There are two (2) funding opportunities through this unique award mechanism; an individual may apply for only one of these opportunities:

1. Health Equity Research Network (HERN) on Community-Driven Research Approaches – Partner Hub
   Required pre-proposals due by Tuesday, March 26, 2024
   The key outcome of this HERN is the establishment of new models for community-driven research that can be scaled and used as a foundation for shifting norms, paradigms and practices within all domains of health research. Each Partner Hub must have two research projects and be represented by a community-based organization and an academic institution. The collaborations between and among the Partner Hubs build momentum around both systems change and knowledge of a particular issue, making it an ideal mechanism to meet the interrelated objectives.  
    
2. Health Equity Research Network on Community-Driven Research Approaches – Community Engagement Resource Center
   Required pre-proposals due by Thursday, March 28, 2024
   The Community Engagement Resource Center (CERC) will, under leadership of the Director, incorporate a multidisciplinary approach to provide capacity building, training, evaluation, and the management of a Community of Practice for the full Network. The CERC will facilitate engagement across the Partner Hubs and service as a coordinating center, facilitating capacity building, study optimization, communication, evaluation, and a Community of Practice. 

This funding mechanism will establish a collaborative, multi-center network with a specific focus on innovative methodological approaches for community-driven research and developing new scalable models for doing research differently, with greater shared authority with CBOs. The Network will create, implement, and make available to the broader scientific community a body of evidence- driven approaches that will support academic and community-based partners in working as equal partners to conduct research that meets the needs of the local community.  Specific deliverables will include a “playbook” of best practices for community-driven research and a compendium of published materials and key outcomes.  In addition, through opportunities provided to the program the training of trainees, this mechanism will help to develop the next generation of researchers and CBO staff who are experienced in working collaboratively to promote the health and well-being of all individuals in their communities.

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UArizona may submit one pre-application.

AHA Membership Requirement: Any individual applying as a Center Director or a Project Principal Investigator (PI) must be an AHA Professional Member before submitting a full proposal. (Membership is not required to submit a pre-proposal.) Join or renew when preparing an application in ProposalCentral, online, or by phone at 301-223-2307 or 800-787-8984. Membership processing may take 3-5 days; do not wait until the application deadline to renew or join.

Required Pre-Proposal 

Each Center Director is required to send a pre-proposal USE THIS LINK to provide the following:

• Name and institution of the Center Director and each Project PI
• Center title, and title and performance site of each proposed project

If required, the mechanism through which partnering requirements are being met. See “Additional Expectations and Opportunities” and “Institutional Eligibility/Location of Work” sections.

As part of the required Pre-Proposal, if the submitting institution or a partnering institution is not a research-intensive institution of higher learning, the lead for that institution must upload a letter from a Senior Institutional Official (e.g., president, provost, dean, etc.) indicating they meet the definition of a non-research-intensive institution as stated in the “Additional Expectations and Opportunities” section. 

AHA staff will review for compliance. A non-complying institution will not be permitted to submit a full proposal. This administrative review is part of the Pre-Proposal process, which is required and, though rare, may prevent an applicant from moving forward. Even though the Pre-Proposal is required, each Center and Project applicants should begin planning and designing their applications before the Pre-Proposal deadline to maximize the amount of time available to develop their full proposal.

Purpose
The American Heart Association (AHA) announces this Request for Proposals for the Strategically Focused Research Network (SFRN) on Inflammation in Cardiac and Neurovascular Disease.

THE ROLE OF INFLAMMATION IN CARDIAC AND NEUROVASCULAR DISEASE

Throughout the body, inflammation plays a crucial role in maintaining tissue homeostasis and initiating appropriate immune responses against pathogens or injury. However, dysregulation of inflammatory processes can lead to detrimental effects, contributing to the development and progression of many disease states, such as autoimmune conditions, cancer, diabetes, kidney disease and liver disease.1

The heart and nervous system are also subject to disease with dysregulation of the inflammatory system. Inflammatory myocarditis, characterized by inflammation of the myocardium, is more likely to occur in males compared to females.2 It is most commonly triggered by viral infection; triggering viruses include adenoviruses, enteroviruses, parvoviruses and coronaviruses (including SARS-CoV-2), among others.3  Less commonly, myocarditis is caused by bacterial or fungal infection or autoimmune diseases.  Of more recent note, it was discovered during the COVID-19 pandemic that vaccines developed against SARS-CoV-2, particularly those using mRNA technology, elicited myocarditis in a subset of vaccine recipients.4 The highest incidence (approximately 50 / 100,000) was found in men under 40. 

Myocarditis can be subclassified based on a number of characteristics. The most prominent symptoms are chest pain and dyspnea,5 and in many cases, myocarditis may resolve on its own. One notable exception is fulminant myocarditis, a rare and severe form of myocarditis that is responsible for a high proportion of cardiac-related deaths in young individuals.6 Acute myocarditis is defined as that for which symptoms are of recent onset, generally within a month or so. Inflammatory processes associated with myocarditis, such as infiltration of immune cells, release of pro-inflammatory cytokines, and oxidative stress, can lead to myocyte damage, fibrosis, and impaired contractility.3,7-8 Myocarditis that is associated with cardiac dysfunction and remodeling of the ventricle is referred to as inflammatory cardiomyopathy, a condition that is typically irreversible. It may result in arrhythmias, ventricular dysfunction or heart failure and requires lifelong therapy and/or heart transplant.

Within the nervous system, inflammation has been implicated in an array of pathologies, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.9-10 Inflammation also plays a prominent role in stroke.11-13  A robust neuroinflammatory response is initiated following an ischemic event. Sex differences are also observed with stroke, with the risk being higher for females than males.14 The primary cause of this neuroinflammation is the activation of immune cells in the brain, including microglia and astrocytes. These cells are responsible for defending the brain against pathogens and injuries. However, under certain conditions, they can become overactivated and release inflammatory molecules. Neuroinflammation can have both beneficial and detrimental effects. In acute situations, neuroinflammation helps clear pathogens, promote tissue repair, and support the restoration of normal brain function. However, chronic or excessive neuroinflammation can damage neurons, impair synaptic communication, break down the blood-brain barrier, and disrupt the delicate balance of the brain's environment.11

CARDIOTOXICITY 
Cardiotoxicity describes a condition wherein a decrease in cardiac function results from administration of drugs or other agents. Currently, the term is largely identified with changes in cardiovascular function resulting from treatment with a number of cancer therapies. Whereas a decrease in left ventricular ejection fraction is the cardiac parameter most closely aligned with cardiotoxicity, additional cardiac effects (e.g., left ventricular systolic dysfunction, angina, and acute coronary syndrome) may also be characterized as cardiotoxicity.15 

There are several potential mechanisms underlying cardiotoxicity of chemotherapeutic agents, including inflammation. For example, use of chemotherapeutics of the anthracycline class, widely prescribed because of their efficacy against both solid and hematologic tumors, is associated with a high incidence of cardiotoxicity.16 Despite this effect of anthracyclines being described decades ago, the mechanism(s) underlying cardiotoxicity are not fully elucidated. Studies in more recent years do suggest, however, that at least part of the cardiotoxic actions of anthracyclines are related to inflammation.17 In addition, pre-clinical studies assessing effects of anti-inflammatory agents against anthracycline-induced cardiotoxicity have shown favorable results.18-19  Targeting inflammation thus holds promise for preventing or mitigating cardiotoxic effects of this class of chemotherapeutic. 

More contemporary cancer treatments also elicit adverse cardiac effects. Immune checkpoint inhibitors (ICIs), a new and promising class of anti-cancer drugs, may elicit a severe form of myocarditis.20 Whereas the incidence is relatively low, the mortality rate is high, due in part to the fact that many individuals present with a fulminant-like form of myocarditis. The mechanism underlying ICI-induced myocarditis remains unclear. The promise of this new class of cancer treatment will not be fully realized unless the mechanism is identified, which will facilitate therapeutic strategies to prevent or mitigate this severe adverse effect.   

While our understanding of the role inflammation plays in cardiac and brain dysfunction has grown considerably in recent years, several hindrances remain that preclude improved recognition and treatment of these conditions. For instance, significant gaps remain in understanding of the downstream signaling events and potential crosstalk; development of new animal and in vitro models would support these needs. In addition, notable opportunities for optimization of diagnostic capabilities exist, such as identification and assessment of biomarkers with improved specificity and development of improved imaging techniques. Clinical trials designed to assess outcomes more specifically for distinct types and/or stages of inflammatory conditions are also needed. 

C. Glembotski