National Heart, Lung, and Blood Advisory Council June 2022 Meeting Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

MEETING SUMMARY OF THE NATIONAL HEART, LUNG, AND BLOOD ADVISORY COUNCIL

June 14, 2022

The 297th meeting of the National Heart, Lung, and Blood Advisory Council (NHLBAC) convened virtually and in person on Tuesday, June 14, 2022. The meeting began in a closed session that started at 10:00 a.m. and ended at 11:07 a.m. The open session convened at 12:16 p.m. and ended at 3:12 p.m. Dr. Gary H. Gibbons, Director of the National Heart, Lung, and Blood Institute (NHLBI), presided as chair.

NHLBAC Members Attending
Victoria L. Bautch, Ph.D.
Mercedes R. Carnethon, Ph.D.
Martha U. Gillette, Ph.D.
Tina V. Hartert, M.D., Ph.D.
David H. Ingbar, M.D.
Edward E. Morrisey, Ph.D.
Kiran Musunuru, M.D., Ph.D.
Richard S. Schofield, M.D. (Ex Officio)
Zachariah P. Zachariah, M.D.

Ad Hoc Members Attending
Lakiea Bailey, Ph.D. (Ad Hoc)
Amanda Mae Fretts, M.D., M.P.H. (Ad Hoc)
Lynn Schnapp, M.D. (Ad Hoc)
Martha C. Sola-Visner, M.D. (Ad Hoc)

Members of the Public Attending
The total number watching online was reported by NIH Videocast to 273.

NHLBI Employees Attending
Several NHLBI staff members were in attendance via Zoom.

CLOSED SESSION

This portion of the meeting was closed to the public in accordance with the determination that it concerned matters exempt from mandatory disclosures under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended.

REVIEW OF APPLICATIONS

The session included a discussion of procedures and policies regarding voting and confidentiality of application materials, committee discussions and recommendations. Members absented themselves from the meeting during discussion of, and voting on, applications from their own institutions or other applications in which there was a potential conflict of interest, real or apparent. Members were asked to sign a statement to this effect. The Council considered and recommended 3,211 applications requesting $7,107,864,374 in total costs. For the record, it is noted that secondary applications were also considered en bloc.

REVIEW OF INTRAMURAL RESEARCH

A report prepared by the Board of Scientific Counselors (BSC), NHLBI, on the NHLBI staff and intramural laboratories was presented to the Council by Dr. Donald M. Bers, BSC Chair.

OPEN SESSION

I. CALL TO ORDER

Dr. Gibbons called the meeting to order at 12:16 p.m. in an Open Session. He welcomed Advisory Council members, NHLBI staff, and public attendees to the Open Session of the meeting.

II. ADMINISTRATIVE ANNOUNCEMENTS

Dr. Laura K. Moen (Director, Division of Extramural Research Activities, NHLBI) noted that the meeting would be publicly broadcast and archived on videocast. She reviewed the agenda.

III. REPORT OF THE DIRECTOR

Dr. Gibbons addressed elements of accountable stewardship and scientific opportunities that are in accordance with NHLBI priorities.

Accountable Stewardship. Dr. Gibbons reviewed NHLBI’s fiscal year 2022 (FY 2022) budget. During the appropriation hearings, the appropriators expressed interest in the issues of the
 
long-term effects of COVID-19, the next generation, health disparities, maternal morbidity and mortality, climate change and health, and structural racism—topics that align with NHLBI priorities. NHLBI’s FY 2022 appropriations represent an increase of 3.9 percent over FY 2021, in keeping with rising appropriations for NIH. This budget increase allows NHLBI to pursue its priorities in promoting investigator-initiated science. The number of R01 awards grew in 2022, although the overall success rate decreased slightly due to an increase in the number of applications. As part of NHLBI’s commitment to the next generation, the Institute was able to sustain a success rate for early-stage investigators in the mid-thirties and a robust success rate for K awards.

Advancing Scientific Priorities. NHLBI is committed to building on the vigorous scientific legacy of its Department of Intramural Research (DIR). Dr. Robert Balaban, who has served as the Director of DIR for 20 years, plans to step down as Director to return to research, and a search for his replacement is ongoing. Dr. Gibbons noted that Dr. Balaban is an excellent scientist, and his research focuses on mitochondrial biology, taking a systems biology approach, and using state-of-the-art optical techniques. Dr. Balaban’s greatest legacy for the intramural research program is the team of talented, diverse young investigators he has recruited. This legacy and many other accomplishments have transformed and reengineered the intramural program.

Dr. Gibbons also informed the Council about:

• NHLBI efforts to translate discovery science into public health impact. He pointed out that NHLBI embraces the social ecological model of health, which recognizes the multilevel inputs to the social determinants of health. Building on lessons learned from the pandemic, NHLBI’s Community Engagement Research Initiative creates a research platform to advance health equities. NHLBI is extending the model developed for COVID-19 by the Community Engagement Alliance (CEAL) to advance health equity in the trans-NIH initiatives in maternal health and climate and health.
   
• NHLBI actions to advance its global health research portfolios for public health impact. He noted that rates of noncommunicable diseases are rising globally, on track to dominate the global disease burden. Low- and middle-income countries are struggling with rising rates of noncommunicable diseases. NHLBI is a global leader in heart, lung, blood, and sleep research, particularly in the strategic areas of chronic lung disease, hypertension, and sickle cell disease (SCD). Dr. Gibbons highlighted the work led by Dr. George A. Mensah (Director, Center for Translation Research and Implementation Science, NHLBI) to drive the implementation of NHLBI’s global health agenda, including through participation in the multinational Global Alliance for Chronic Diseases (GACD) Multimorbidity Research Program, which addresses hypertension, among other concerns. He noted that investments in Sub-Saharan Africa provide an opportunity to translate SCD interventions that have proven to be effective in the United States to address SCD mortality, particularly in children. NHLBI is engaging scientists in Africa to build capacity for screening, clinical research, and treatment of SCD. Hopefully, this infrastructure will provide settings for new curative technologies in Sub-Saharan Africa. Curing SCD will require broad collaboration among institutions. NHLBI is building a community of practice that focuses on the most vulnerable populations in the United States and the world to the tackle heart, lung, blood, and sleep disorders.

IV. LOCATION MATTERS: UNEXPECTED ROLES FOR THE COMPLOSOME IN HEALTH AND DISEASE

Dr. Claudia Kemper (Section Chief, CIRS, DIR, NHLBI) introduced the complosome and provided an overview of the CIRS research program, which uses new pre-clinical model systems and therapeutic modulation to understand the regulation and function of the complosome, as well as its role in disease. CIRS’s goals are to answer two simple questions—how the complosome functions and how it is regulated—that have complex answers. They found that the complosome operates in all immune cells, and perturbations in the complosome across immune cells drive human diseases from infection to autoimmunity to sterile inflammation.
Normalization of Th1 and macrophage hyperactivity in vitro points to the complosome being amenable to pharmacological intervention. CIRS is collaborating with the pharmaceutical industry in evaluating a cell-permeable drug that targets intracellular C3.

In parallel to attacking an intracellular target, CIRS is seeking to understand cell surface regulation of C3 and C5 gene transcription. Researchers found that tissue-resident immune cells have a complosome gene expression signature, and the integrin lymphocyte function- associated antigen 1 (LFA-1) is the master regulator of immune cell C3 induction. This finding led to a refined model of complosome engagement and activities in which circulating immune cells move into tissue, receive a signal from LFA-1, and have induction of effector function.
Immune cells undergo Th1 cell contraction when the pathogen danger is cleared. Further research in the scientific community has found that the complosome is not immune cell specific. CIRS has collaborated on studies regarding the importance of the complosome in colon cancer and severe COVID-19.

Dr. Kemper presented selected snapshots of ongoing work in her laboratory, which uses cutting-edge technologies in the interdisciplinary study of the interface of innate and adaptive immunity. The lab developed a new single-cell RNA sequencing (sc-RNA-seq) pathway analysis tool and is using it to define new Th1 shutdown pathways. CIRS researchers found that Th1 contraction is controlled at the translational rather than the transcriptional level. They are studying the balance between Th1 induction and shutdown and are also investigating the role of the complosome in CD4+ and CD8+ T cell memory.

In addition, CIRS researchers are focusing on the CD46 receptor, which is expressed in different isoforms with distinct cytoplasmic domains (CYT-1 and CYT-2). When they are cleaved, they are hypothesized to interact with transcription factor complexes. CIRS researchers are studying the molecular mechanisms of CD46-mediated Th1 induction and have identified proteins that interact with CYT-1 in the cytosol and have found CYT-1 target genes in the nucleus. The top DNA motif in the CYT-1 bound regions was the SP/KLF family. C46 was found to regulate gene expression via chromatin remodeling. CIRS scientists are developing a small animal model of C46 deficiency using the zebrafish. More that 90 percent of C46-deficient zebrafish die at a young age, and survivors develop cardiomyopathy.

Also, researchers in Dr. Kemper’s laboratory are studying the role of the complosome in meningeal immunity. Dr. Kemper concluded that the complosome is not fully explored. The intracellular complement system might explain why therapeutics have been unsuccessful and indicates that targeting the cellular complement might be a new way to treat chronic inflammatory disease states. NHLBI DIR is the ideal research environment for this effort.

V. NHLBI CONCEPT CLEARANCE

NHLBI staff presented 21 concepts for clearance. Members of the Advisory Council were asked to rate the concepts on six criteria using Decision Lens.

Titles: The Pediatric Heart Network Renewal (UM1); The Pediatric Heart Network Renewal (U24)

Description: These two concepts support the renewal of the Pediatric Heart Network (PHN), funding a Coordinating Cluster and multiple clinical centers. PHN’s objective is to
improve patient outcomes through clinical trials and studies of congenital heart disease (CHD) and other pediatric heart diseases across the lifespan. The renewal will build on PHN’s initial strengths, focus on precision medicine, explore disparities in outcomes, and apply big data science.

Title: Renewal of the Sudden Death in the Young Initiative 2024-2028 (R01, N01, IAA)

Description: This concept renews support for a collaborative initiative with the National Institute of Neurological Disorders and Stroke and the Centers for Disease Control and Prevention. It is designed to address critical knowledge gaps in the epidemiology and causes of sudden death in the young and to inform prevention efforts. Key changes to enhance the program are surveillance of disparities, collection of biospecimens, and engagement in strategies to support diversity of data in the registry.

Titles: Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE) Renewal - Coordination Center (U24 Clinical Trial Not Allowed); Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE) Renewal - Summer Institutes (R25 Clinical Trial Not Allowed); Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE) Renewal - Notice of Special Interest (NOSI): Administrative Supplements for Small Research Program (SRP) Pilot Awards (U24)

Description: These three concepts renew support for the trans-NIH PRIDE program. PRIDE focuses on the recruitment of a cohort of summer scholars, mentor-mentee matching, assistance in grantsmanship, administration of small research program pilot grants, and evaluation of the program’s impact. Continuation of this program will stimulate the entry of new research investigators from historically excluded and underrepresented groups into the pipeline across existing and emerging areas of science relevant to NHLBI’s mission.

Title: Limited Competition: Small Grant Program for NHLBI K01/K08/K23/K25 Recipients (R03 Clinical Trial Optional)

Description: This concept renews support for a small grant program designed to expand the research objectives and help the transition to research independence of current and recent NHLBI K award grantees. This program has proven successful in increasing the application and success of rate of grantees in obtaining R01-equivalent grants and helping them achieve their stated goals. Minor changes that will benefit awardees include an increase in direct costs and addition of the K25 grant mechanism.

Title: Secondary participation in Catalyst Award for Early-Stage Investigators (ESIs) Pursuing Research on HIV Comorbidities, Coinfections, and Complications (DP1- Clinical Trial Optional)

Description: This concept supports participation in a trans-NIH initiative that falls under NHLBI’s HIV/AIDS program. Its goal is to fund creative, early-stage research on HIV comorbidities, coinfections, and complications to support the next generation of researchers. It arose from a portfolio analysis that revealed a critical decline in junior investigators involved in HIV research.

Title: (Renewal/Secondary Participation) ORWH SCORE Program Specialized Centers of Research Excellence on Sex Differences (U54 Clinical Trial Optional)

Description: This concept supports the Specialized Centers of Research Excellence on Sex Differences (SCORE) program, a trans-NIH initiative led by the Office of Research on Women’s Health. The Centers have research projects and an administrative core. This program funds translational research on sex differences and applies across all NHLBI mission areas.

Title: Dissemination and Implementation Research in Health (R01 Clinical Trial Optional)

Description: This concept supports a trans-NIH funding opportunity for dissemination and implementation research focusing on underserved populations in the United States and abroad. This funding opportunity bridges the gap between research and policy by building a knowledge base about integrating health information, effective innovations, and new clinical practice guidelines and tools into a broad range of healthcare settings.

Titles: Secondary Participation in FIC International Research Training Award (NCD-LIFESPAN) Program (D43 – Clinical Trial Optional); Secondary Participation in FIC Emerging Global Leader Award (K43 Independent Clinical Trial Required); Secondary Participation in FIC Emerging Global Leader Award (K43 Clinical Trial Not Allowed)
 
Description: These three concepts support trans-NIH global health research capacity building. These funding announcements, issued by the Fogarty International Center (FIC), support collaborative research training between U.S. and low- and middle-income country institutions. The goal of this program is to develop evidence-based interventions relevant to a given country’s setting for noncommunicable diseases across the lifespan.

Title: Secondary Participation to Implementation Research to Reduce Non-communicable Disease (NCD) Burden in Low- and Middle-Income Countries and Tribal Nations During Critical Life Stages and Key Transitions (R01 Clinical Trial Optional)

Description: This concept relates to the GACD Multimorbidity Program. This global program with trans-NIH participation supports implementation and multimorbidity research to reduce the noncommunicable disease burden in low- and middle-income countries, as well as for the first time in Native American and Alaska Native populations. High-income partner countries also will focus on their indigenous populations. This program seeks to overcome barriers to implementing evidence-based innovations, tools, policies, strategies, and guidelines. This concept focuses on critical life stages and key transitions.

Titles: Secondary Participation to Implementation Research to Reduce Non-communicable Disease (NCD) Burden in Low- and Middle-Income Countries and Tribal Nations in Urban Environments (R01 Clinical Trial Optional); Secondary Participation to Implementation Research to Reduce Non-communicable Disease (NCD) Burden in Low- and Middle-Income Countries and Tribal Nations in Urban Environments (R61/R33 Clinical Trial Required)

Description: These two concepts relate to the GACD Multimorbidity Program, emphasizing risks and exposures linked to urbanization and related health inequities. They seek to develop environmentally sustainable innovations.

Titles: Secondary Sign-on to GACD Multimorbidity Research: Chronic Disease Prevention Across the Lifespan (R01 Clinical Trial Optional); Secondary Participation to Leveraging Implementation Research for Chronic Disease Prevention Across the Lifespan (R61/R33 Clinical Trial Required)

Description: These two concepts focus on multimorbidity research conducted by the GACD program. They support implementation research that aims to improve integrated care for patients with noncommunicable disease multimorbidities in low- and middle-income countries and underserved communities in high-income countries across the lifespan.

Title: Build UP Trust Prize Challenge (N01)

Description: This concept’s objective is to increase research participation and adoption of existing and new tools and strategies by improving engagement with underserved populations. This trans-NIH funding initiative engages directly with nontraditional innovators, including underserved community members who do not traditionally apply for NIH grants. Its two phases are first to solicit new ideas and second to implement proposed solutions.

Titles: Secondary Sign On: SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late-Stage Development (SB1 Clinical Trial Not Allowed, R42, R44); Secondary Sign On: SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late-Stage Development (SB1 Clinical Trial Required, R42, R44)

Description: These two concepts support reauthorization of a trans-NIH program to expand commercialization readiness. They support late-stage technical assistance and research and development activities. Positive outcomes from these funding opportunities have included the development of cellular therapies, an ultrasound system, and SARS-CoV-2 diagnostics.

CLOSING REMARKS

Dr. Gibbons adjourned the meeting at 3:16 p.m.