Lindsey Barske, PhD

Patterning of cartilaginous condensations in the developing facial skeleton

Adult endochondral bones resemble much larger versions of their initial cartilage templates, which in turn mimic the shape of their generative precartilaginous condensations. How these early condensations are shaped prior to their near-isometric growth is fundamental to understanding the basis of skeletal form. Using the simple larval zebrafish facial skeleton as a model, we used new lineage-tracing tools to definitively show that precartilaginous condensations themselves originate from neighboring clusters of cells termed mesenchymal condensations. We hypothesized that the position of each mesenchymal condensation determines the axis of growth of its corresponding precartilaginous condensation, thus influencing its final shape. Consistent with this idea, we find that positive Fgf and inhibitory Jagged-Notch signals intersect to precisely position a mesenchymal condensation below the ear, with loss of pathway function leading to predictable shape changes in the resulting cartilage element (the homolog of the stapes). Deciphering the array of signals that control the spatial distribution of mesenchymal condensations thus offers a promising approach to understanding the origins of skeletal form.

Bahram Namjou-Khales, MD

Multiancestral polygenic risk score for pediatric asthma

In the last two decades, the identification of thousands of single-nucleotide polymorphisms (SNPs) for common complex diseases or traits occurred because of genome-wide association studies (GWAS). By calculating a weighted sum of the trait-associated alleles for each individual, constructing a polygenic risk score (PRS) reflects an individual’s estimated genetic predisposition for a given phenotype. In this study, we developed a polygenic risk score for asthma using state of the art Bayesian regression framework method. This platform uses the most comprehensive GWAS data set (Trans-National Asthma Genetic Consortium) summary statistics as a discovery set, and the two large biorepositories of electronic medical records and genomics (eMERGE) and the UK biobank as training and validation cohorts to construct a multi-ancestral PRS score. The constructed PRS successfully predicts disease status in different ancestries and age groups with high performance. The next step involved performing a phenome-wide association study (PheWAS) to evaluate the pleiotropy and shared genetic etiology of the developed PRS with other complex phenotypes.

Amelle Shillington, DO

Psychiatric-genetics inpatient care delivery model improves access to clinical genetic evaluation, testing and diagnosis for patients with neurodevelopmental disorders.

Neurodevelopmental disorders, including autism spectrum disorder, intellectual disability and global developmental delay, are among the most common indications for referral to clinical genetics evaluation. Clinical genetic testing is a necessary course of action for people with neurodevelopmental disorders.

There are known barriers to accessing clinical genetics evaluation for patients with neurodevelopmental disorders. Thus we created a collaborative psychiatric–genetics consultation service and psychiatric–genetics outpatient clinic with the goal to improve genetics care delivery in tandem with psychiatric care providers.

Two years after the launch of this pilot program, our data demonstrate improved access to genetics evaluation, with shorter wait times and fewer patients lost to follow-up. Perhaps most importantly, new genetic diagnoses changed medical care for the majority of patients.

Ying Sun, PhD

Treatment of a genetic brain disease by CNS-wide microglia replacement

The use of hematopoietic cell transplantation following myeloablation conditioning to treat various genetic metabolic syndromes is largely ineffective in diseases affecting the brain due to low myeloid cell incorporation into the central nervous system. Development of a novel approach for efficient microglia replacement in rodents uses circulation-derived myeloid cells. The cells broadly incorporated in the brain and generated microglia-like cells more efficiently than bone marrow transplant. In a Gaucher disease mouse model of progressive neurodegeneration, circulation-derived myeloid cells-mediated microglia replacement reduced cell loss and brain inflammation, improved motor behavior and extended life span. The proof-of-concept study suggests this approach might be therapeutic in multiple neurological conditions and highlight microglial cells as an effective cellular target for cell-based regenerative therapies to restore brain function.

Stephen Waggoner, PhD

Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues.

Natural killer (NK) cells limit vaccine efficacy by culling a fraction of responding T cells early in the immune response. Overcoming this immunosuppressive function of NK cells would be an innovative strategy to enhance the capacity of vaccines to trigger antibody and cellular immune responses of sufficient quality to prevent infections with HIV and other pathogens. In this study, we discovered a link between the immunosuppressive activity of NK cells to transient re-localization of these cells in T- and B-cell-rich follicles of lymphoid tissues. This localization and suppression of T cells required CXCR3 on NK cells. Vaccines that trigger robust interferon responses stimulate up-regulation CXCR3 ligands to promote NK-cell regulation of vaccine responses. These results identify a migratory mechanism of NK cells that can target the enhancement of vaccine efficacy.