2021 |
Casanova, Jean-Laurent Zhang, Qian Zhang, Shen-Ying |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inborn Errors of Immunity in Patients With Life-Threatening Covid-19
Project Summary There is immense interindividual clinical variability in humans infected with SARS-CoV-2, ranging from silent infection to lethal COVID-19. The first breakthrough to crack this enigma came from the field of inborn errors of immunity (IEI). In an international cohort of 659 patients, we reported 23 patients with IEIs at eight influenza susceptibility loci that govern TLR3- and IRF7-dependent type I interferon (IFN) immunity (3.5%), including four unrelated patients with autosomal recessive IRF7 or IFNAR1 deficiency. We also reported an additional 101 patients with neutralizing autoantibodies (auto-Abs) against type I IFN (10.2% of 987), who were auto-immune phenocopies of the patients with IEI. Interestingly, 94% of the patients with auto-Ab against type I IFN were men, and one of the six sick women had X-linked dominant incontinentia pigmenti (IP), suggesting X-linked inheritance in at least some of the patients. Collectively, these patients account for about 13.5% of life-threatening COVID- 19 cases studied. We now hypothesize that other IEI that result in abnormal (i) production or amplification of type I IFN, (ii) activity of soluble type I IFNs (via neutralizing auto-Abs), or (iii) response to type I IFN (in terms of interferon stimulated gene (ISG) activity), can underlie life-threatening COVID-19 in other patients. To tackle these three specific aims, we benefit from an international recruitment from the COVID Human Genetic Effort (https://www.covidhge.com). Our preliminary data are very strong. First, we have found 215 patients with predicted loss-of-function (pLOF) variants at 157 loci associated with production or amplification of type I IFN, including one patient homozygous for a pLOF variants in NLRC3, two patients heterozygous for pLOF variants in DDX58/RIG-I, and six patients heterozygous for pLOF variants in subtypes of type I or III IFNs. Second, among patients with auto-Ab against type I IFN, we identified a patient hemizygous for a pLOF in X-linked SASH3. In addition, we found that 25% of patients with IP, which is associated with severely skewed X-inactivation, have auto-Ab against type I IFN, further suggesting an X-linked basis of auto-Ab to type I IFN production. Third, we found 24 patients with pLOF variants in 18 ISGs. We have shown that the international path-breaking program we established in only 6 months is highly efficient, as it resulted in a paradigm-shifting discovery. Our new program will benefit from this momentum. Our future discoveries of new inborn errors of type I IFN immunity underlying life-threatening COVID-19 pneumonia will pave the way for new diagnostic and therapeutic strategies to better manage patients infected with SARS-CoV-2 at risk of severe disease. Selected patients may benefit from subcutaneous or nebulized IFN-a or IFN-b (defect in type I IFN production or amplification), plasmapheresis and/or B cell depletion (neutralizing auto-Abs against type I IFNs), or other therapies, including mAbs against SARS-CoV-2 (defects of ISGs).
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0.943 |
2022 — 2025 |
Hughes, Roxanne Peterson, Karen Olukeye, Abimbola Zhang, Qian |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Brite Girls Online Stem Practices: Building Relevance and Identity to Transform Experiences @ Florida State University
Despite decades of policies and programs meant to increase the representation of girls and women in science, technology, engineering, and mathematics (STEM), girls and women of color still represent a much smaller percent of the STEM workforce than they do in the US population. This lack of representation is preventing the US STEM workforce from reaching its true potential. Intersecting inequalities of gender, race, ethnicity, and class, along with stereotypes associated with who is successful in STEM (i.e., White men), lead to perceptions that they do not belong and may not succeed in STEM. Ultimately, these issues hinder girls’ STEM identity development (i.e., sense of belonging and future success), lead to a crisis of representation for women of color and have compounding impacts on the STEM workforce. Research suggests there are positive impacts of in-person STEM learning after-school and out-of-school time programs on girls’ sense of belonging. The increasing need for online learning initiated by the COVID-19 pandemic means it is vital to investigate girls’ STEM identity development within an online community. Thus, the project will refine and test approaches in online learning communities to make a valuable impact on the STEM identity development of girls of color by 1) training educators and role models on exemplary approaches for STEM identity development; 2) implementing a collaborative, girl-focused Brite Online Learning Community that brings together 400 girls ages 13-16 from a minimum of 10 sites across the United States; and 3) researching the impact of the three core approaches -- community building, authentic and competence-demonstrating hands-on activities, and interactive learning with women role models -- on participating girls’ STEM identities in online settings.<br/><br/>The mixed methods study is guided by guided by Carlone & Johnson’s model of STEM identity involving four constructs: competence, performance, recognition, and sense of belonging. Data collection sources for the quantitative portion of the project include pre- and post-surveys, while qualitative data sources will be collected from six case study sites and will include observations, focus group interviews with girls, artifacts created by girls and educators, educator interviews, and open-ended survey responses. This approach will enable the research team to determine how and the extent to which the Brite Online Learning Community influences STEM identity constructs, interpreting which practices lead to meaningful outcomes that can be linked to the development of STEM identity for participating girls in an online environment. The products of this work will include research-based, tested Brite Practices and a toolkit for fostering girls’ interest, identification, and long-term participation in STEM. The resulting products will increase the reach of informal STEM education programming to girls of color across the nation as online spaces can reach more girls, potentially increasing the representation of women of color in the STEM workforce. This project is funded by the Advancing Informal STEM Learning (AISL) program which seeks to advance new approaches to, and evidence-based understanding of, the design and development of STEM learning in informal environments.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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