Because the adult heart cannot regenerate or repair itself, the end result of ischemic heart disease (IHD) is often progression of acute myocardial infarction (AMI) to congestive heart failure (CHF) resulting in the death of over 41,000 persons annually. Currently, medical interventions to prevent the progression to heart failure following a severe AMI are limited. Treatment options for end-stage CHF are even more limited. A new therapeutic option in development, cellular cardiomyoplasty (CCM), or transplantation of autologous primary skeletal muscle cells into the myocardium, offers potential for augmenting cardiac function in myocardial disease. The overall aim of this project is to develop a basis for the use of cellular cardiomyoplasty in cardiac disease including AMI and CHF. The hypothesis is: in a rabbit model of myocardial infarction, decreased myocardial performance can be at least partly reversed by repopulating the damaged area with primary skeletal myoblasts to re- form a functional unit within an infarct region.
The specific aims to test this hypothesis are to: 1) optimize marker gene expression in autologous primary skeletal muscle myoblasts to follow their fate in the heart; 2) compare the efficiency of tow methods of myoblast delivery to rabbit heart: localized delivery via direct injection or more dispersed delivery via infusion onto the coronary circulation; 3) use load-insensitive in dices of regional cardiac function to determine the temporal effects of directly injected myoblasts on regional contractile function and on ventricular morphology in control and infarcted hearts; 4) determine the temporal effects of myoblasts infused into the coronary circulation on global contractile function (by 2-d echocardiography) and ventricular morphology in control and infarcted hearts. Accomplishing these aims should allow an evaluation of the extent to which autologus skeletal myoblasts can survive implantation into the cardiac environment and contribute to cardiac function. Developing cellular cardiomyoplasty may contribute a promising therapeutic intervention for IHD or CHF both of which are major economic and management problems for all health care providers because of the substantial health care costs expended in the treatment of these severely debilitating conditions and because of the limitations of definitive therapeutic interventions. R02MH49428 There is abundant evidence to suggest that neuropsychiatric disorders such as schizophrenia and autism are caused in many cases by genetic abnormalities that affect development and function of forebrain neural systems involved in cognition and emotion. The largest structures of the forebrain are the cerebral cortex and the striatum; both have been implicated as having a role in neuropsychiatric disorders. The goal of my research is to understand how genes regulate development of the striatum. To this end, my laboratory has identifies the D1x genes, which encoded a family of homeodomain transcription factors that are candidates for having a central role in striatal development. There are four known D1x genes that are expressed in the embryonic forebrain.
The aims of the experiments proposed in this grant application are focused on: (1) elucidating the sequence of these genes and their encoded proteins; (2) characterizing the biochemical properties of the DLX proteins; (3) determining whether the DLX proteins are transcriptional regulators; (4) identifying proteins that interact with and modulate the function of the DLX proteins; (5) determining the intracellular location of the DLX proteins; (6) determining the temporal and spatial patterns expression of the D1x RNAs and proteins in the prenatal and postnatal forebrain; (7) begin to determine where the D1x genes are in the genetic hierarchy that regulates development of the forebrain using ectopic expression experiments.
| van den Bos, Ewout J; Thompson, Richard B; Wagner, Anja et al. (2005) Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging. Eur J Heart Fail 7:435-43 |
| Thompson, Richard B; Parsa, Cyrus J; van den Bos, Ewout J et al. (2004) Video-assisted thoracoscopic transplantation of myoblasts into the heart. Ann Thorac Surg 78:303-7 |
| van den Bos, Ewout J; Davis, Bryce H; Taylor, Doris A (2004) Transplantation of skeletal myoblasts for cardiac repair. J Heart Lung Transplant 23:1217-27 |
| Cherwek, D H; Hopkins, M B; Thompson, M J et al. (2000) Fiber type-specific differential expression of angiogenic factors in response to chronic hindlimb ischemia. Am J Physiol Heart Circ Physiol 279:H932-8 |
| Atkins, B Z; Hueman, M T; Meuchel, J et al. (1999) Cellular cardiomyoplasty improves diastolic properties of injured heart. J Surg Res 85:234-42 |
| Atkins, B Z; Hueman, M T; Meuchel, J M et al. (1999) Myogenic cell transplantation improves in vivo regional performance in infarcted rabbit myocardium. J Heart Lung Transplant 18:1173-80 |
