The NIH Pathway to Independence Award, also known as the K99/R00, helps early-career scientists transition from a postdoctoral training position to that of an independent investigator. Considered one of the most prestigious funding opportunities available for both domestic and international fellows, the award provides funding for one to two years of postdoctoral training and three years of independent research as a principal investigator.
Read below for more information about this year’s NICHD award-winning projects, plus a fun fact about each K99 recipient.
Diana Elizondo, PhD
“Delineation of macrophage-derived transglutaminases' role in adipose tissue health and inflammation in obesity.”
Unhealthy obesity is characterized by impaired adipose tissue growth and function, and altered inflammatory states. Invariably, this condition promotes the development of metabolic disorders. Although the pathological burden is well established, the underpinning molecular mechanics that drive deregulation of immunometabolic activities remain unclear. We show that transglutaminases are novel soluble modulators of immunometabolism that can shift obesity into a metabolically unhealthy state. Importantly, we identified macrophages as key sources of transglutaminases in obesity—thereby extending the importance of the transglutaminase-producing macrophage subsets as pivotal players governing the shift towards unhealthy obesity. We hypothesize that myeloid-cell derived transglutaminases serve as pivotal modulators in balancing obesity health. To address this hypothesis, we will evaluate the mechanisms by which transglutaminases regulate adipose tissue health in obesity via employment of vector-based delivery of shRNA silencing of transglutaminases in diet-induced obese mice in vivo. Concomitantly, we will develop a novel lentiviral-based conditional knockout mouse model, as a tool to concretely evaluate the role of transglutaminase-producing immune cells in modulating the immunometabolic environment of obesity. Completion of this work will unravel the immunometabolic regulatory network orchestrated by specific transglutaminase-producing immune cell subsets in modulating the adipose tissue microenvironment during obesity.
Leah Greenspan, PhD
“Dissecting vascular reperfusion and remodeling after injury in zebrafish”
Two percent of the total US population is plagued by open chronic wounds, with defective vascular reperfusion acting as a major contributor to failed wound closure. Delayed vascular regrowth and remodeling after cutaneous injury is prevalent in aging and diabetic adults, but the mechanisms that are altered under these conditions are not well understood. I have established a new reproducible cutaneous wound model in zebrafish using a rotary tool. Using this injury system along with the long-term live imaging capabilities of adult zebrafish and the many novel tools available in this model, I seek to uncover how changes in endothelial cell responses to cutaneous injury contribute to the vascular defects seen in aging and diabetic wounds compared to normal vessel development and regrowth. My studies will reveal key regulators of vascular regrowth after injury and provide crucial insights toward establishing new vascular reparative therapies.
Joyce Thompson, PhD
“The role of transcription factor co-binding in regulating progenitor plasticity and lineage emergence during mammalian embryogenesis”
All mammalian life begins as a single cell. During the course of development, this single cell is transformed into a multicellular embryo comprising of an entire repertoire of cell-lineages. Defects in the formation of any of these lineages lead to developmental anomalies and can even be detrimental in some cases. My research focuses on understanding how the first few cell-lineages of life arise from common progenitor populations, in the very early mouse embryo. By employing genomics assays my research aims to decipher how transcription factors regulate the genome to orchestrate the timely and accurate emergence of cell-lineages during embryonic development.
Jarred Whitlock, PhD
“Resolving the mechanism of osteoclast multinucleation and signaling in bone remodeling”
Bones are living tissues, continuously remade on-site by teams of multinucleated osteoclasts that resorb old bone and osteoblasts that deposit new bone. The number of nuclei within a multinucleated osteoclast determines its resorption capacity, and many skeletal pathologies—such as fibrous dysplasia, osteopetrosis, osteoporosis, and metastatic bone disease—are underpinned by perturbations in the number/size of osteoclasts, resulting in skeletal dysfunction in more than 200 million individuals. Gaps in our fundamental understanding of how osteoclasts form, function, and coordinate with osteoblasts to maintain skeletal integrity have stymied the identification of novel, targeted therapies. My lab will uncover a mechanistic understanding of how osteoclasts form, function, and coordinate with osteoblasts by exploiting a protein manager of osteoclast formation and rare disease models as guides. Filling these fundamental gaps in the understanding of skeletal biology will provide a battery of mechanistic targets to tune osteoclast function, promote bone regeneration, and address the growing metabolic skeletal pathology in our aging population.
Shu Yang, PhD
“How does the GATOR2 complex regulate lysosomal functions?”
Lysosomes are central to metabolic homeostasis. They are the main organelles that break down macromolecules to provide nutrients such as amino acids for cell growth. Lysosomes protect cells by digesting excess or unwanted cell parts. They also destroy invaded pathogens such as bacteria or viruses and help to trigger programmed cell death under certain conditions. Lysosomal functions and physiology are tightly controlled by upstream signaling pathways. The MiT/TFEs transcriptional factor family promotes the transcription of a program of lysosomal and autophagic genes and is often deregulated in cancer. I discovered that the GATOR2 complex, an activator of the metabolic regulator TORC1, maintains lysosomal function by protecting MiT/TFEs from proteasomal degradation independent of TORC1 signaling. I determined that in GATOR2 knockout cells, members of the MiT/TFEs family are degraded by the proteasomes, resulting in lysosome dysfunction. Additionally, I demonstrated that the GATOR2-dependent regulation of MiT/TFEs is conserved in pancreatic ductal adenocarcinoma and in translocation renal cell carcinoma and has roles in promoting the growth of those cancer cells. My research interest is to investigate the detailed mechanisms of this GATOR2-dependent regulation of MiT/TFEs, and how this pathway affects cancer metabolism.