RFA-DK-20-021 Mechanistic Studies of SARS-CoV-2/COVID-19 in NIDDK - PowerPoint PPT Presentation

RFA-DK-20-021 Mechanistic Studies of SARS-CoV-2/COVID-19 in NIDDK Diseases and Organ Systems Maren R. Laughlin maren.laughlin@nih.gov 301-594-8802 Program Director, Division of Diabetes, Endocrinology and Metabolic Diseases David Saslowsky david.Saslowsky@nih.gov 301-594-8876 Bonnie Burgess-Beusse bonnie.burgess-beusse@nih.gov 301-594-4726 Program Director, Division of Digestive Diseases and Nutrition Ivonne H. Schulman Ivonne.Shulman@nih.gov 301-435-3350 Afshin Parsa Afshin.parsa@nih.gov 301-827-1375 Program Director, Division of Kidney, Urologic, and Hematologic Diseases Xiaodu Guo guox@niddk.nih.gov 301-594-4719 Scientific Review Officer Todd Le LeT@extra.niddk.nih.gov 301-594-7794 Grants Management Specialist Michael Mensah michael.mensah@nih.gov 301-594-3308 Scientific Program Analyst

Background • Obesity, older age and male sex are all associated with poor COVID-19 outcomes. • Diseases, including diabetes (odds ratio 1.48, 16 studies) and chronic kidney disease (odds ratio 3.25, 9 studies) are associated with a significantly greater risk of mortality from COVID-19. (metanalysis by Paddy Ssentongo et al, PLoS One, August 2020) • Among other organs, COVID-19 infection is resulting in acute and possibly chronic damage and dysfunction in heart, kidney and liver. (review by Dominik Wolff et al, Infection, August 2020) • Minority and disadvantaged populations are particularly adversely affected by COVID-19, with elevated incidence, severity and mortality. 2

Purpose To generate pilot data and establish a strong premise for future studies that will lead to treatment and prevention of severe outcomes in COVID-19 patients with NIDDK diseases, or in tissues of interest to NIDDK. 3

RFA-DK-20-021 • Support new basic and clinical mechanistic research on SARS-CoV-2 and COVID-19 within NIDDK’s interests, including: Diabetes and other metabolic diseases, obesity, and endocrine, digestive, liver, pancreas, kidney, urological, and hematologic tissues and diseases • Identify biological mechanisms surrounding: • Role of pre-existing diseases • Adverse acute or chronic outcomes in NIDDK tissues / diseases, including new onset of disease 4

RFA-DK-20-021 •Does not support interventional clinical trials •Applications focused on pathways of viral infection, invasion, and shedding, without consideration of pathogenic consequences to NIDDK-relevant host organs/tissues/cells will be determined non-responsive to the RFA 5

RFA-DK-20-021 Mechanistic Studies of the Interaction between SARS-CoV-2/COVID-19 and Diseases and Organ Systems of Interest to NIDDK (R01 Clinical Trial Optional) Trans-NIDDK RFA Budget: $250,000 DC/year Issued: July 10, 2020 Duration: 3 years Due: December 16, 2020 $5M/year (11-13 awards) Council: May 2021 Reduced emphasis on preliminary data Will support studies in human subjects or model organisms, using isolated tissues, cells, or in vivo approaches. 6

RFA-DK-20-021 Diabetes, Metabolic and Endocrine Diseases • Mechanisms for any increased susceptibility or altered course of COVID-19 due to type 1 or type 2 diabetes or diabetic complications; • Roles of dysregulated glycemia, insulin resistance , insulin secretion, etc. in severity of response to COVID-19 infection; • Mechanisms whereby COVID-19 infection results in acute or chronic metabolic dysfunction, or the onset of diabetes or other endocrine diseases; • Mechanisms involved in alterations in the course of existing type 1 or type 2 diabetes or the complications of diabetes following COVID-19 infection.

RFA-DK-20-021 Obesity and Nutrition • Tissues, biological systems and pathways involved in increased susceptibility, greater severity, or diminished response to treatment for COVID-19 in obesity ; • Aspects of adipose tissue biology involved in the severity of COVID-19 infection, disease course, response to treatment, and outcomes in obesity; • Mechanisms for impact of nutritional status on variability in COVID-19 susceptibility, course, and response to treatment; • Do diet-host-microbiome interactions impact the course of COVID-19 infection?

RFA-DK-20-021 Digestive Diseases and Liver Diseases • Mechanisms by which SARS-CoV-2/COVID-19 induces disease flares, exacerbates disease activity, or contributes to adverse disease outcomes in patients with underlying digestive diseases (including gastrointestinal and liver diseases) ; • Determining how SARS-CoV-2 may induce diarrhea, nausea, and vomiting ; • Does SARS-CoV-2 induce pathology in GI and liver cell types/organs that express SARS-CoV-2 viral receptors? • How does SARS-CoV-2 interact with the enteric nervous system to worsen GI diseases within the mission of the Division of Digestive Diseases and Nutrition or spread to other organs or the central nervous system?

RFA-DK-20-021 Kidney and Urologic Diseases • Factors and mechanisms by which renal disease portends worse COVID-19 related morbidity and mortality ; • Factors and mechanisms by which COVID-19 might uniquely increase the incidence or severity of acute kidney injury ; • Does SARS-CoV2 cause direct kidney injury and if so, to which cells and by which mechanisms? • Mechanisms by which COVID-19 may negatively impact renal function and related outcomes in individuals with renal transplants or glomerulonephritis ; • Effects of COVID-19 on the structure and function of urologic organs.

RFA-DK-20-021 Hematologic Diseases • Mechanisms by which COVID-19 and cytokine dysregulation alter hematopoietic stem and progenitor cell proliferation or function (e.g. myeloid blood cell production or tissue macrophage function); • Biologic pathways and mechanisms that contribute to a significantly altered course of COVID-19 sequelae in cohorts of inherited cytopenias .

RFA-DK-20-021 Pertaining to HIV/AIDS • In patients that are co-infected with SARS-CoV-2 and HIV/AIDS, it is a priority to understand the mechanisms by which organs and tissues that manifest diseases relevant to the NIDDK mission are negatively impacted by SARS-CoV- 2/COVID-19

Frequently Asked Questions • Can I propose to validate a clinical biomarker for predicting disease severity?  No, that would not fall into the realm of mechanistic studies. • Do I need to include preliminary data?  No, this RFA doesn’t require preliminary data. However, you should be able to demonstrate that the project is feasible and will have a significant outcome. • May I propose a project for 5 years and >$250,000 direct costs/year?  No, but such a project can be submitted to the normal R01 competition, as long as it has sufficient preliminary data.

RFA-DK-20-021 Mechanistic Studies of SARS-CoV-2/COVID-19 in NIDDK Diseases and Organ Systems Maren R. Laughlin maren.laughlin@nih.gov 301-594-8802 Program Director, Division of Diabetes, Endocrinology and Metabolic Diseases David Saslowsky david.Saslowsky@nih.gov 301-594-8876 Bonnie Burgess-Beusse bonnie.burgess-beusse@nih.gov 301-594-4726 Program Director, Division of Digestive Diseases and Nutrition Ivonne H. Schulman Ivonne.Shulman@nih.gov 301-435-3350 Afshin Parsa Afshin.parsa@nih.gov 301-827-1375 Program Director, Division of Kidney, Urologic, and Hematologic Diseases Xiaodu Guo guox@niddk.nih.gov 301-594-4719 Scientific Review Officer Todd Le LeT@extra.niddk.nih.gov 301-594-7794 Grants Management Specialist Michael Mensah michael.mensah@nih.gov 301-594-3308 Scientific Program Analyst