Lei Ding - US grants

Effective robotic assistance of infants with or at risk of developing Cerebral Palsy (CP) has the potential to reduce the significant functional limitations as well as the potential deficits in cognitive development. This project focuses on the development and testing of a sequence of robotic assistants that promote early crawling, creeping, and walking, along with a model of infant-robot interaction that encourages the continued practice of movement patterns that will ultimately lead to unassisted locomotion. Typically developing infants initially learn to crawl through the generation of spontaneous limb and trunk movements. Early in the process, these spontaneous movements transport the infant across the floor. The rewarding locomotory experience drives the infant to refine the movements to intentional and exploratory skills. Ultimately, the infant intentionally engages these skills to solve larger problems, such as obtaining an interesting toy or exploring the environment. Infants with conditions such as CP lack the muscle strength, postural control, and motor coordination necessary for these early exploratory limb and trunk movements to result in locomotion. Without this positive feedback, the development of the neural pathways for productive limb use is diminished, which results in delayed or lack of development of crawling and walking. These limitations in mobility negatively affect other domains of development such as perception and cognition, with effects being visible even into adulthood.

The robotic assistants to be developed in this project will aid the infant in developing locomotory skills by selectively supporting a portion of his/her weight and providing artificial, rewarding locomotory experiences. The PI's approach to infant-robot interaction is to first instrument the infant with a set of sensors, allowing for reconstruction of the trunk and limb positions in real time. A semi-supervised clustering process will then identify a menu of canonical spatio-temporal limb and trunk movement patterns given observations of behavior that is exhibited by children who are either typically developing or at risk of developing CP. The robot will respond to the recognition of a canonical movement by assisting in the corresponding postural support and transport of the child. The PI's hypothesis is that this positive feedback will encourage the continued practice of the canonical movements, as well as their use in solving larger problems. The infant-robot interaction model will selectively reward specific canonical movements as different levels of capabilities are exhibited. As the child becomes proficient at using a simple movement to trigger robotic assistance, the robot will reduce (and ultimately eliminate) its response to that particular canonical movement. Other canonical movements that encode related, but more complex and/or coordinated limb movements, will continue to be available. As the limb movements are mastered the vertical support will be reduced to encourage the infant to bear more of his/her own weight. The hypothesis is that this early intervention approach will help to guide the child along a progressive developmental trajectory that will end with locomotory skills and muscle strength that require little or no assistance. EEG-based neuroimaging will be used to monitor the progression of the infant's development. The hypothesis is that the degree of proficiency of certain skills will be identifiable using the EEG index related to motor output. This information will be used to guide the semi-supervised clustering process, as well as the decision process for selectively rewarding certain canonical movements.

Broader Impacts: Equipping children with CP at an early age with locomotory skills will not only bring them more in line with typically developing children, but will also reduce their reliance on long-term care while increasing their success in self-help, in education, and in the workplace. The techniques will be applicable to a range of other childhood disorders (including Down Syndrome), to retraining patients following stroke, and to the creation of tunable gestural interfaces for intelligent prostheses.

? DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) maintain homeostasis of the blood and immune system throughout life. They are tightly regulated by their microenvironmental niche in the bone marrow. Mounting evidence suggests that chronic myeloid leukemia (CML) arise from mutant HSCs. These diseased leukemia stem cells (LSCs) hijack the HSC mechanisms to sustain the cancer growth and cause relapse. Eradication of LSCs is thus pivotal to cure CML. The discovery of the causing active Bcr/abl kinase mutation in CML and the development of tyrosine kinase inhibitors against Bcr/abl have revolutionized the way we treat CML. Tyrosine inhibitors become the first line of treatment against CML. Although tyrosine kinase inhibitors (e.g. imatinib) can manage the disease, they do not eliminate CML-SCs. A major CML-SC resistant mechanism is the protection offered by the bone marrow niche. Elucidating the niche regulatory mechanisms and target the niche protection mechanisms will help eliminate CML-SCs to better treat CML. However, little is known about the LSC niche. The goal of the proposed research is to characterize how thrombopoietin (TPO), an extrinsic factor, regulates HSCs and LSCs. TPO pathway is required for primitive HSC maintenance in mice and humans. It is not known where Tpo-expressing bone marrow cells create a special niche for primitive HSCs. Furthermore it is not known whether TPO pathway is `hijacked' by CML-SCs for their maintenance. Here, we will identify cellular source of TPO in the bone marrow. Then we will test what cells represent functionally important source for HSC maintenance in vivo. Finally, we will functionally test the role of TPO in CML progression with the focus on CML-SCs in vivo. The results of these studies are expected to not only provide new insights on how the bone marrow niche regulates HSC self-renewal and function, but also have the potential to identify therapeutic targets for CML in the niche.

Project summary/Abstract Hematopoietic stem cells (HSCs) persist throughout life to generate all blood cells. The microenvironmental niche critically regulates HSCs. The bone marrow is the major organ where adult HSCs reside. Rapid progress has been made regarding the nature and mechanisms of the bone marrow HSC niche. Interestingly, HSCs change tissues and niches during development and in stress. The fetal liver is the major hematopoietic organ where HSCs self-renewal rapidly. Around birth, the liver loses HSC-supporting activity and HSCs egress to seed the bone marrow. The liver can become hematopoietic and support HSCs in extramedullary hematopoiesis (EMH) in stress and some hematologic diseases. However, in contrast to the bone marrow, little is known about the liver HSC niche during development and in stress. Our preliminary data identified stellate cells as a novel key component of the fetal liver HSC niche in vivo. In addition, we have identified a transcriptional factor, Lhx2, that is required for the proper cell fate of stellate cells as the niche cell for HSCs in the fetal liver. The goal of the proposed research is to leverage our knowledge of the fetal liver niche to elucidate the role of Lhx2 in stellate cells during development. We will also study the nature and mechanisms of the adult EMH liver niche. The results of these studies are expected to not only provide new insights on how the liver niche regulates HSCs, but also have the potential to identify mechanisms mediating the generation of new niches to amplify HSCs for clinic use.

Project summary/Abstract Understanding and targeting abnormal tumor microenvironment is critically important for developing effective therapy. Primary myelofibrosis (PMF) is a form of myeloproliferavtie neoplasm (MPN) that often progresses to lethal leukemia. Treatment options are limited for PMF, and the only potential cure, stem cell transplantation, is prohibitively toxic for most patients. Thus, novel and effective therapies are in great need for PMF. Recurrent mutations resulting in abnormal activation of the JAK-STAT pathway have been shown to be the driver of the disease. As a result, JAK inhibitors have been developed to treat PMF. However, these inhibitors only reduce some constitutional symptoms without significant impact on disease-causing leukemia stem cells (LSCs). A deeper understanding of the pathogenesis of PMF will offer the opportunity to better treat the disease. The bone marrow niche is a critical component to the pathogenesis of PMF. Our preliminary data show that bone marrow LepR+ stromal cells are the source of fibrosis. We have also identified several key mediators of LepR+ cell fibrosis. In this proposal, we propose to elucidating the cellular and molecular mechanisms of how LSCs interact with the fibrotic niche in vivo. We will test whether targeting the fibrosis mediators will lead to efficient elimination of LSCs and have synergistic effects with JAK inhibitors. By having a deeper understanding of the interaction between LSCs and the niche, our strategy of targeting the diseased niche may provide novel therapeutics to PMF.