(3ao) Enhancing Contractility in Heart Failure: An Alternative & Safer Approach through Pkc? Inhibition

Heart Failure (HF) is marked by a deficiency in the ability of heart to pump sufficient blood in response to systemic demands. This results in a persistent negative feedback through enhancing the expression of catecholamines and other neuroendocrine factors. Enhancing cardiac output could disrupt this negatively reinforcing circuit thus leading to a secondary reduction in neuroendocrine drive. Though traditional inotropes can selectively enhance the myocardial contractility unfortunately, clinical trials in humans show increased mortality. Thus, the safety of traditional inotropes in clinical settings is debatable. For this, PKCα may represent a more refined and milder target. Inhibiting, PKCα can lead to 20-30% increase in contractility. It seems that loss of PKCα activity may augment cardiac contractility precisely within the physiological limits thus may be providing a safer alternative target for end-stage HF. Here, I investigate the question that why PKCα activity is increased and maintained despite the presence of an elaborate braking system? Using, a systems biology approach, I show that the local DAG signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during the normal systolic and diastolic cardiac function. A novel two-compartment computational model is proposed for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in the identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.

Teaching Interests:

I believe that teaching is a central part of an academic career. I derive my teaching philosophy

from my experience as a teaching assistant, design lecturer and senior project supervisor at

University of South Florida. This experience was further enhanced when I developed and taught

several new graduate courses in systems biology of disease during my postdoctoral fellowship at

University of Texas.

1. Experience

During first two years (2000-2002) of my graduate studies, I have served as a teaching assistant

for several courses in chemical and biomedical engineering, including capstone course of process

and product design, introduction to biomedical engineering, process engineering, chemical

reaction engineering and graduate course of computer-aided process engineering (CAPE). Based

on my student evaluations and prior industrial experience, faculty at chemical and biomedical

engineering department decided to appoint me as a lecturer and senior project supervisor for the

capstone course of process and product design. For next three years (2002-2005), I independently

taught this course and also supervised the senior design projects for almost two hundred students.

This experience has helped me deepening my knowledge in these areas. By assisting and

supervising individual students in their assignments and projects, I gained experience in what the

common challenges are for most students acquiring knowledge.

As an instructor in-charge for the process and product design course at the University of South

Florida, I relished the opportunity to work with students one-on-one in order to assess what they

understood well and what they did not understand based on lectures alone. This experience made

it clear to me that different students learn differently, and sometimes simply expressing a concept

in an alternative fashion was enough to make the concept clear. It also motivated me to develop

different types of instruction in order to give the students the best opportunity to learn. I therefore,

incorporated several different instructional mechanisms, including traditional lectures, active learning discussions, student-led presentations, discussions in small groups, interaction with

industry experts, plant visits along with traditional problem sets.

Seniors in the design course are also required to complete a design project. This was a great

opportunity for me to expose students to more practical aspects of the profession. I developed and

assigned the design projects based on the complex process research challenges of local industries

in South Florida. That way not only the students could learn in a more realistic setting but also

has the opportunity to find employment based on their work. During my stay at South Florida, I

took the initiative to develop partnerships with local process industries so that my students can

taste the flavor of reality in their design education. These projects also provided an opportunity

for students to plan, manage, execute and evaluate themselves as individuals and team players. I

used to meet with each design group once a week for one hour and have also asked them to

develop a work plan for their project with self-imposed deadlines. I administered these projects

according to industry protocols like reporting the man-hours, writing the memos, compiling the

report, etc.

As a postdoctoral fellow (2005-2010), I have been fortunate enough to be asked to develop and

teach graduate-level courses related to my research in systems biology. During this period, I

taught courses like systems biology of cardiac disease and computational neuroscience. These

courses were intended for students who have diversified backgrounds in medicine, biology,

engineering (such as medical doctors, molecular biologists and biomedical engineers) and are

interested in scientific computation. The number of students enrolling in these courses was

usually between 8/9. In these courses, I taught students the concepts and structures of computer

programming (matlab), some non-numerical and numerical algorithms; concepts of cell signaling

and how to formulate signaling models with minimum availability of data. Teaching these

courses gave me lots of experience in how to teach an introductory course in systems biology. I

also learned how to tutor students one-to-one or how to give a lecture in a graduate course with

only a few students.

2. Personal Philosophy

I believe that learning is a complex process that is individual, content and context specific. As an

instructor I am always attentive to these factors and adapt my instructional strategy according to

the needs of learners, subject matter and setting. I believe it is important to develop a learning

partnership with students such that they have no hesitation in communicating or approaching

instructor. In my classes, I encourage students to participate actively. For example, I encourage

them to ask questions. According to my years’ experience as a student, I think many students

refrains from asking questions because they are afraid of appearing stupid in front of their peers.

Hence, sometimes I ask some very easy questions on purpose to build their confidence. I always

highly comment their questions as good questions. My goals of teaching can be summarized as:

Firstly, the student should have learned how to solve the fundamental problem in question with

the basic techniques taught in the course. Secondly, the student should have gained an overview

of the subjects covered by the course. Thirdly, the student should have gained enough

methodology to be able to learn advanced and complex topics independently if necessary. In the

classes I taught, I have always tried to meet the goals as mentioned above. For example, in the

capstone course of process and product design, I spent considerable time to introduce them the

design concepts and algorithms along with basic understanding of economic and feasibility

models. Each theory lecture is followed by a computer lab session in which related problems are

solved through active learning mode. As students understand the basic components of product

and process design, it is not difficult for them to transit from simple to complex problems in

design. I also show students a systematic approach to complex design problem and how to apply

simulation techniques to real-life chemical and biomedical engineering problems by examples.

This requires sophisticated simulation skills, which are little advanced for undergraduate students.

However, students like these types of problems because they are convinced that learning how to

simulate and design a complex process/product design challenge does matter to their future

professional activities. I really enjoy seeing that students in my classes are very willing to learn.

When my lectures went well, students asked the right questions at the right time. This really

stimulates the desire of my teaching, and I feel rewarded.

In addition to the core chemical engineering courses, I look forward to teaching the systems

biology course, which provide opportunities for understanding the complexity in cellular

signaling cascades and identification of new drug targets. I am also interested in developing new

courses or contributing to existing offerings in the areas of biochemical engineering, metabolic

engineering and synthetic biology. I would also be very interested in creating new laboratory

experiments for existing courses or new laboratory courses in the areas of systems and synthetic

biology.